JP2013522171A - Compounds and their therapeutic uses - Google Patents

Abstract

The present invention treats cancer, systemic or chronic inflammation, rheumatoid arthritis, diabetes, obesity, T cell mediated autoimmune diseases, ischemia, and other complications associated with these diseases and disorders For the use of compounds, pharmaceutical compositions and methods. The present invention relates generally to the field of medicinal chemistry. In particular, the present invention provides compounds that inhibit nicotinamide phosphoribosyltransferase (Nampt). The invention also provides methods of making these compounds, pharmaceutical compositions containing these compounds, and methods of using these compounds to treat diseases that preferably respond to inhibition of Nampt.

Description

(Field of Invention)
The present invention relates generally to the field of medicinal chemistry. In particular, the present invention provides compounds that inhibit nicotinamide phosphoribosyltransferase (Nampt). The present invention also provides methods of making these compounds, pharmaceutical compositions containing these compounds, and diseases using these compounds that preferably respond to inhibition of Nampt (particularly cancer, systemic or chronic). Of inflammation, rheumatoid arthritis, diabetes, obesity, T cell mediated autoimmune diseases, ischemia and other complications associated with these diseases and disorders).

(Background of the Invention)
Nicotinamide phosphoribosyltransferase (Nampt, also known as visfatin and pre-B-cell colony-enhancing factor 1 (PBEF)), nicotinamide (NaM) is converted to 5-phosphoribosyl- Catalyze condensation with 1-pyrophosphate to give nicotinamide mononucleotide. This is the first rate-limiting step in one biosynthetic pathway that cells use to make nicotinamide adenine dinucleotide (NAD ⁺ ).

NAD ⁺ has many important cellular functions. Classically, NAD ⁺ serves as a major coenzyme in metabolic pathways, in which NAD ⁺ is between its oxidized form (NAD ⁺ ) and its reduced form (NADH). Constantly changing. More recently, NAD ⁺ has been shown to be involved in maintaining genomic integrity, stress response, and Ca2 ⁺ signaling, where NAD ⁺ is a poly (ADP-ribose) polymerase (PARP) , Sirtuin, and cADP-ribose synthase are consumed by enzymes, respectively (reviewed in Non-Patent Document 1).

As an important coenzyme in the redox reaction, NAD ⁺ is required in glycolysis and citrate cycles. Here, NAD ⁺ accepts the generated high energy electrons and passes these electrons to the electron transport chain as NADH. This NADH-mediated supply of high-energy electrons is the driving force behind oxidative phosphorylation (a process in which most of ATP is generated in aerobic cells). As a result, having a sufficient level of NAD ⁺ available in the cell is important for maintaining proper ATP levels in the cell. As can be appreciated, reduction of cellular NAD ⁺ levels due to Nampt inhibition can ultimately be expected to result in ATP depletion and eventually cell death.

  In view of the above, it is probably not surprising that inhibitors of Nampt are being developed as chemotherapeutic agents for the treatment of cancer. In fact, two Nampt inhibitors are currently in clinical trials for the treatment of cancer (Non-patent document 2; Non-patent document 3; Non-patent document 4; and Non-patent document 5).

  As a result, it not only inhibits Nampt and can be used to treat cancer, but also systemic or chronic inflammation, rheumatoid arthritis, diabetes, obesity, T-cell mediated autoimmune diseases, ischemia, and these There is a clear need for compounds that can also be used in the treatment of other complications associated with diseases and disorders.

Belenky, P. et al., NAD + metabolism in health and disease. Trends Biochem. Sci. 32, 12-19 (2007) Holen, K. et al. The pharmacokinetics, toxicities, and biologic effects of FK866, a nicotinamide adenine dinucleotide biosynthesis inhibitor.Invest.New Drugs. 26,45-51 (2008) Hovstadius, P. et al. A Phase I study of CHS 828 in patients with solid tumor malignancy. Clin. Cancer Res. 8, 2843-2850 (2002) Ravaud, A. et al., Phase I study and pharmacokinetic of CHS-828, a guanidino-containing compound, administered orally as a single dose every 3 weeks in solid tumours: an ECSG / EORTC study.Eur.J.Cancer.41,702-707 (2005) von Heideman, A. et al. Safety and efficacy of NAD depleting cancer drugs: results of a phase I clinical trial of CHS 828 and overview of published data. Cancer Chemother. Pharmacol. (2009) Sept. 30 [Epub ahead of print]

(Simple Summary of Invention)
The present invention provides compounds that inhibit the activity of Nampt. These compounds treat cancer, systemic or chronic inflammation, rheumatoid arthritis, diabetes, obesity, T cell-mediated autoimmune diseases, ischemia, and other complications associated with these diseases and disorders Can be used.

  Specifically, the present invention provides compounds of formula I

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式Iにおいて、Y、Y₁、Y₂、およびZ₀は、本明細書中で以下に定義されるとおりである。

And the pharmaceutically acceptable salts and solvates thereof, wherein Y, Y ₁ , Y ₂ , and Z ₀ are as defined herein below. .

  The present invention further provides Formula II

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIにおいて、Y、Y₁、Y₂、Y₃、およびZは、本明細書中で以下に定義されるとおりである。

And the pharmaceutically acceptable salts and solvates thereof, wherein Y, Y ₁ , Y ₂ , Y ₃ , and Z are as defined herein below. It is.

  The present invention further provides Formula III

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIIにおいて、Y、Y₁、Y₂、Y₃、およびY₄は、本明細書中で以下に定義されるとおりである。

And the pharmaceutically acceptable salts and solvates thereof, wherein in formula III, Y, Y ₁ , Y ₂ , Y ₃ , and Y ₄ are defined herein below. It is as follows.

  The present invention further provides Formula IV

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IVにおいて、o、p、q、Y、Y₁、Y₂、Y₃、およびY₄は、本明細書中で以下に定義されるとおりである。

And the pharmaceutically acceptable salts and solvates thereof, wherein in formula IV, o, p, q, Y, Y ₁ , Y ₂ , Y ₃ , and Y ₄ are as defined herein As defined below.

  As mentioned above, the present invention inhibits the activity of Nampt and thus cancer, systemic or chronic inflammation, rheumatoid arthritis, diabetes, obesity, T cell mediated autoimmune diseases, ischemia, and these Provided are compounds that can be used in the treatment of other complications associated with other diseases and disorders. Thus, in a related aspect, the invention is also related to cancer, systemic or chronic inflammation, rheumatoid arthritis, diabetes, obesity, T cell mediated autoimmune disease, ischemia, and these diseases and disorders. A method for treating other complications is provided, wherein the method is by administering to a patient in need of such treatment a therapeutically effective amount of one or more compounds of the invention.

  For the treatment of cancer, systemic or chronic inflammation, rheumatoid arthritis, diabetes, obesity, T cell mediated autoimmune diseases, ischemia and other complications associated with these diseases and disorders There is also provided the use of a compound of the invention for the manufacture of a medicament useful for treatment. Furthermore, the present invention also provides a pharmaceutical composition having one or more of the compounds of the present invention and one or more pharmaceutically acceptable excipients. In addition, in a method of treating cancer, systemic or chronic inflammation, rheumatoid arthritis, diabetes, obesity, T cell mediated autoimmune diseases, ischemia, and other complications associated with these diseases and disorders Also contemplated is a method by administering a pharmaceutical composition of the present invention to a patient in need of such treatment.

  Furthermore, the present invention relates to cancer, systemic or chronic inflammation, rheumatoid arthritis, type 2 diabetes, obesity, T cell mediated autoimmune diseases, ischemia, and other complications associated with these diseases and disorders. Further provided are methods of treating symptoms associated with symptoms or delaying the onset of these symptoms. These methods comprise an effective amount of one or more of the compounds of the invention, preferably in the form of a pharmaceutical composition or medicament, in cancer, systemic or chronic inflammation, rheumatoid arthritis, type 2 diabetes, Administration to individuals having or at risk of developing obesity, T cell mediated autoimmune diseases, ischemia, and other complications associated with these diseases and disorders.

  The compounds of the invention can be used in combination therapy. Therefore, associated with cancer, systemic or chronic inflammation, rheumatoid arthritis, type 2 diabetes, obesity, T cell mediated autoimmune diseases, ischemia and other complications associated with these diseases and disorders Also provided are methods of combination therapy for treating symptoms or delaying the onset of these symptoms. Such methods may be used in patients in need thereof with one or more of the compounds of the present invention, and together or separately, at least one other anti-cancer treatment, anti-inflammatory treatment, anti-chronic joint. Administering a rheumatic treatment, an anti-type 2 diabetes treatment, an anti-obesity treatment, an anti-T cell mediated autoimmune disease treatment, or an anti-ischemic treatment.

  The advantages and features of the above and other embodiments of the present invention, and the manner in which they are accomplished, will become more readily apparent when the following detailed description of the invention is considered in conjunction with the accompanying examples. . The examples illustrate preferred exemplary embodiments.

  Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

  Other features and advantages of the invention will be apparent to those skilled in the art from the following detailed description and the following claims.

FIG. 1 (A) illustrates how the activities of Nampt and PARP are interconnected via different actions in their NAD ⁺ / NaM cycle. Figure 1 (B) shows how PARP activation in BRCA-proficient cells, due to certain types of DNA damage, caused the conversion of NAD ⁺ to nicotinamide (NaM) Illustrates whether Nampt activity is required for NAD ⁺ rescue. FIG. 1 (C) illustrates how PARP inhibitors and Nampt inhibitors can cooperate to cause cell death in BRCA-deficient cells that require PARP for survival.

(Detailed description of the invention)
1. Definitions As used herein, the term “alkyl”, when used herein alone or as part of another group, unless otherwise specified, is from 1 to 20 Number of carbon atoms (whenever appearing herein, a numerical range such as “1-20” refers to each integer within the given range. For example, “1-20 carbon atoms” Means that the alkyl group may consist of 1, 2 or 3 carbon atoms, or more carbon atoms, up to a total of 20). A branched chain group. The alkyl group may be unsubstituted or substituted with one or more substituents (generally 1 to 3 except for halogen substituents (eg perchloro)). Substituents may be present). For example, a C _1-6 alkyl group is a straight or branched aliphatic group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert- Butyl, 3-pentyl, hexyl and the like), which may be optionally substituted.

  As used herein, “lower alkyl” refers to an alkyl group having 1 to 6 carbon atoms.

The term “alkylene” as used herein has from 1 to 20 carbon atoms and has 2 points of attachment (ie, a “divalent” chain), saturated aliphatic A hydrocarbon straight-chain or branched-chain group is meant. For example, “ethylene” represents the group —CH ₂ —CH ₂ — and “methylene” represents the group —CH ₂ —. An alkylene chain group can also be considered a plurality of methylene groups. For example, ethylene contains two methylene groups. The alkylene group may also be in an unsubstituted form or a form substituted with one or more substituents.

The term “alkenyl” as used herein, alone or as part of another group, has at least one double bond between two of the carbon atoms in the chain. Means a straight or branched divalent chain group of 2 to 10 carbon atoms (unless otherwise specified). An alkenyl group may also be in an unsubstituted form or a form substituted with one or more substituents (generally 1 except for halogen substituents (eg perchloro or perfluoroalkyl)). To 3 substituents). For example, a C _2-6 alkenyl group contains _2-6 carbon atoms and has a straight chain or at least one double bond between two of the carbon atoms in the chain or A branched chain group (eg, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl, which may be optionally substituted).

  The term “alkenylene” as used herein refers to an alkenyl group having two points of attachment. For example, “ethenylene” represents the group —CH═CH—. The alkylene group may also be in an unsubstituted form or a form substituted with one or more substituents.

The term “alkynyl”, as used herein, alone or as part of another group, is a straight chain of 2 to 10 carbon atoms (unless otherwise specified). Or a branched-chain group in which at least one triple bond is present between two of the carbon atoms in the chain. An alkynyl group may be unsubstituted or substituted with one or more substituents (generally one except in the case of halogen substituents (eg perchloro or perfluoroalkyl)). ~ 3 substituents). For example, a C _2-6 alkynyl group contains 2 to 6 carbon atoms, which can be optionally substituted, and has at least one triple bond of carbon atoms in the chain. A straight or branched group between two (eg, ethynyl, 1-propynyl, 1-methyl-2-propynyl, 2-propynyl, 1-butynyl and 2-butynyl).

  The term “alkynylene” as used herein means alkynyl having two points of attachment. For example, “ethynylene” represents the group —C≡C—. Alkynylene groups can also be in unsubstituted form or substituted with one or more substituents.

  The term “carbocycle” as used herein, alone or as part of another group, includes cycloalkyl groups and non-aromatic partially saturated carbocyclic groups (eg, cycloalkenyl and Cycloalkynyl). The carbocycle may be in an unsubstituted form or substituted with one or more substituents as long as the resulting compound is sufficiently stable and suitable for use in embodiments of the present invention. Good.

The term “cycloalkyl”, as used herein alone or as part of another group, is a fully saturated 3- to 8-membered cyclic hydrocarbon ring (ie, a cyclic form of alkyl). A single (`` monocyclic cycloalkyl '') or fused to another cycloalkyl, cycloalkynyl, cycloalkenyl, heterocycle, aryl or heteroaryl ring (i.e., adjacent pairs of carbon atoms are Shared with such a ring) ("polycyclic cycloalkyl"). Thus, a cycloalkyl can exist as a monocyclic ring, a bicyclic ring, or a spiral ring. When cycloalkyl is referred to as C _x cycloalkyl, this means that a fully saturated cyclic hydrocarbon ring, which may or may not be fused to another ring, is x carbon atoms. Means a cycloalkyl having When a cycloalkyl is described as being a substituent on a chemical entity, the cycloalkyl moiety is attached to the entity through a single carbon atom in the fully saturated cyclic hydrocarbon ring of the cycloalkyl. Intended to be. Conversely, a substituent on a cycloalkyl can be attached to any carbon atom of the cycloalkyl. A cycloalkyl group can be unsubstituted or substituted with one or more substituents so long as the resulting compound is sufficiently stable and suitable for use in embodiments of the present invention. Examples of cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term “cycloalkenyl” as used herein, alone or as part of another group, is a non-aromatic partially saturated 3- to 8-membered cyclic carbonization having an internal double bond. A hydrogen ring (i.e., a cyclic form of alkenyl), alone (`` monocyclic cycloalkenyl ''), or fused to another cycloalkyl, cycloalkynyl, cycloalkenyl, heterocycle, aryl or heteroaryl ring ( That is, it refers to those that share an adjacent pair of carbon atoms with another such ring) ("polycyclic cycloalkenyl"). Thus, cycloalkenyl can exist as a monocyclic ring, bicyclic ring, polycyclic or helical ring. When cycloalkenyl is referred to as C _x cycloalkenyl, this means that there are _x non-aromatic partially saturated cyclic hydrocarbon rings, which may or may not be fused to another ring. Means cycloalkenyl having carbon atoms; When cycloalkenyl is described as a substituent on a chemical entity, the cycloalkenyl moiety is attached via a carbon atom in the non-aromatic partially saturated ring (with a double bond inside) of the cycloalkenyl. It is intended to be bound to an entity. Conversely, a substituent on a cycloalkenyl can be attached to any carbon atom of the cycloalkenyl. A cycloalkenyl group can be unsubstituted or substituted with one or more substituents. Examples of cycloalkenyl groups include cyclopentenyl, cycloheptenyl and cyclooctenyl.

  The term “heterocycle” (or “heterocyclyl” or “heterocyclic” or “heterocyclo”), when used herein alone or as part of another group, includes carbon atoms, as well as O Means a saturated or partially saturated 3- to 7-membered non-aromatic cyclic ring formed by 1 to 4 heteroatoms independently selected from the group consisting of, N, and S, wherein The nitrogen and sulfur heteroatoms can be optionally oxidized, and the nitrogen can be quaternized as necessary ("monocyclic heterocycle"). The term “heterocycle” also means that the non-aromatic heteroatom-containing cyclic ring is fused to another monocyclic cycloalkyl, cycloalkynyl, cycloalkenyl, heterocycle, aryl or heteroaryl ring (ie, Includes groups ("polycyclic heterocycles") that share a pair of adjacent atoms with such other rings. Thus, a heterocycle can exist as a monocyclic ring, bicyclic ring, polycyclic or helical ring. When a heterocycle is described as a substituent on a chemical entity, it is intended that the heterocycle is attached to the entity via an atom in a saturated or partially saturated ring of the heterocycle. Conversely, substituents on the heterocycle can be attached to any suitable atom of the heterocycle. In a “saturated heterocycle”, the non-aromatic heteroatom-containing cyclic ring is fully saturated, whereas a “partially saturated heterocycle” is one or more independent of the other condensed rings. Double or triple bonds are included in the non-aromatic heteroatom-containing cyclic ring. Heterocycles may be in unsubstituted form or substituted with one or more substituents as long as the resulting compound is sufficiently stable and suitable for use in embodiments of the present invention. Good.

  Some examples of saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl , Isochromanyl group, chromanyl group, pyrazolidinyl group, pyrazolinyl group, tetronoyl group and tetramoyl group.

As used herein, `` aryl '', either alone or as part of another group, is an all-carbon aromatic ring having up to 7 carbon atoms in the ring (`` Monocyclic aryl "). In addition to monocyclic aromatic rings, the term “aryl” is also fused to another cycloalkyl, cycloalkynyl, cycloalkenyl, heterocycle, aryl or heteroaryl ring (ie, adjacent pairs of carbon atoms are All of the above include groups having a carbon aromatic ring ("polycyclic aryl"). When aryl is referred to as C _x aryl, this means that an all-carbon aromatic ring (which may or may not be fused to another ring) has x carbon atoms. , Means aryl. When aryl is described as a substituent on a chemical entity, the aryl moiety is intended to be all bonded to the entity via an atom in the aromatic ring of carbon. Conversely, a substituent on aryl can be attached to any suitable atom of the aryl. Examples of aryl groups include but are not limited to phenyl, naphthalenyl and anthracenyl. The aryl may be in an unsubstituted form or a form substituted with one or more substituents so long as the resulting compound is sufficiently stable and suitable for use in embodiments of the present invention. .

  The term “heteroaryl” as used herein has up to 7 ring atoms and has 1, 2, 3, or 4 heterocycle atoms in the ring (which are Refers to a stable aromatic ring ("monocyclic heteroaryl") having oxygen, nitrogen or sulfur, or combinations thereof. In addition to a monocyclic heteroaromatic ring, the term “heteroaryl” also means that the monocyclic heteroaromatic ring is fused to another cycloalkyl, cycloalkynyl, cycloalkenyl, heterocycle, aryl or heteroaryl ring. (I.e., sharing a pair of adjacent atoms with such other rings) ("polycyclic heteroaryl"). When a heteroaryl is described as being a substituent on a chemical entity, the heteroaryl moiety is intended to be attached to the entity via an atom within the heteroaromatic ring of the heteroaryl. Conversely, a substituent on a heteroaryl can be attached to any suitable atom of the heteroaryl. A heteroaryl can be in an unsubstituted form or a form substituted with one or more substituents so long as the resulting compound is sufficiently stable and suitable for use in embodiments of the present invention. Good.

  Useful heteroaryl groups include thienyl (thiophenyl), benzo [b] thienyl, naphtho [2,3-b] thienyl, thiantenyl, furyl (furanyl), isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl ( phenoxanthiinyl), pyrrolyl (including but not limited to 2H-pyrrolyl), imidazolyl, pyrazolyl, pyridyl (pyridinyl), (including but not limited to 2-pyridyl, 3-pyridyl, and 4-pyridyl), pyrazinyl, Pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinozalinyl, cinnolinyl, pteridylyl, pteridylyl Phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, 1,4-dihydroquinoxaline-2,3-dione, 7-aminoisocoumarin, pyrido [1, 2-a] pyrimidin-4-one, pyrazolo [1,5-a] pyrimidinyl (including but not limited to pyrazolo [1,5-a] pyrimidin-3-yl), 1,2-benzisoxazole- Examples include 3-yl, benzimidazolyl, 2-oxaindolyl and 2-oxobenzimidazolyl. Where the heteroaryl group contains a nitrogen atom in the ring, such nitrogen atom may be in the form of an N-oxide (eg, pyridyl N-oxide, pyrazinyl N-oxide and pyrimidinyl N-oxide).

  As used herein, the term “halo” refers to a chloro, fluoro, bromo, or iodo substituent.

  As used herein, the term “hydro” refers to a bonded hydrogen atom (—H group).

  As used herein, the term “hydroxyl” refers to an —OH group.

As used herein, the term “alkoxy” refers to —O— (C _1-12 alkyl). Lower alkoxy refers to a -O- (lower alkyl) group.

As used herein, the term “alkynyloxy” refers to —O— (C _2-12 alkynyl).

  As used herein, the term “cycloalkyloxy” refers to an —O-cycloalkyl group.

  As used herein, the term “heterocyclooxy” refers to an —O-heterocyclic group.

  As used herein, the term “aryloxy” refers to an —O-aryl group. Examples of aryloxy groups include, but are not limited to, phenoxy and 4-methylphenoxy.

  The term “heteroaryloxy” refers to the group —O-heteroaryl.

  The terms “arylalkoxy” and “heteroarylalkoxy” are used herein to mean an alkoxy group substituted with an aryl group and a heteroaryl group, respectively. Examples of arylalkoxy groups include, but are not limited to, benzyloxy and phenethyloxy.

  As used herein, the term “mercapto” or “thiol” group refers to a —SH group.

  The term “alkylthio” group refers to an —S-alkyl group.

  The term “arylthio” group refers to an —S-aryl group.

  The term “arylalkyl” is used herein to mean an alkyl group, as defined above, that is substituted by an aryl group, as defined above. Examples of arylalkyl groups include benzyl, phenethyl and naphthylmethyl. An arylalkyl group can be unsubstituted or substituted with one or more substituents so long as the resulting compound is sufficiently stable and suitable for use in embodiments of the present invention.

  The term “heteroarylalkyl” is used herein to mean an alkyl group, as defined above, that is substituted by any heteroaryl group. A heteroarylalkyl may be unsubstituted or substituted with one or more substituents so long as the resulting compound is sufficiently stable and suitable for use in embodiments of the present invention.

  The term “heteroarylalkenyl” is used herein to mean any of the alkenyl groups defined above, substituted by any of the heteroaryl groups defined above.

  The term “arylalkynyl” is used herein to mean any of the above defined alkynyl groups substituted by any of the above defined aryl groups.

  The term “heteroarylalkenyl” is used herein to mean any of the alkenyl groups defined above, substituted by any of the heteroaryl groups defined above.

  The term “arylalkoxy” is used herein to mean an alkoxy group substituted by an aryl group as defined above.

  “Heteroarylalkoxy” is used herein to mean any of the above defined alkoxy groups substituted by any of the above defined heteroaryl groups.

  “Haloalkyl” means an alkyl group substituted with one or more fluorine atom, chlorine atom, bromine atom or iodine atom (for example, fluoromethyl group, difluoromethyl group, trifluoromethyl group, pentafluoroethyl group, 1, 1-difluoroethyl group, chloromethyl group, chlorofluoromethyl group and trichloromethyl group).

  As used herein, the term “carbonyl” group refers to a —C (═O) R ″ group, where R ″ is hydro, alkyl, as defined herein. , Cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heterocyclic (bonded through a ring carbon).

  As used herein, the term “aldehyde” group refers to a carbonyl group where R ″ is hydro.

  As used herein, the term “cycloketone” has an acid in which one of the carbon atoms forming the ring is double bonded, ie, one of the ring carbon atoms is —C. A cycloalkyl group that is a (═O) group.

  As used herein, the term “thiocarbonyl” group refers to a —C (═S) R ″ group, where R ″ is as defined herein.

  “Alkanoyl” refers to the group —C (═O) -alkyl.

  The term “heterocyclonoyl” group refers to a heterocyclo group attached to the alkyl chain of an alkanoyl group.

The term “acetyl” group refers to a —C (═O) CH ₃ group.

  “Alkylthiocarbonyl” refers to a —C (═S) -alkyl group.

  The term “cycloketone” means that one of the carbon atoms forming the ring has a double-bonded oxygen, ie one of the ring carbon atoms is a —C (═O) group. It refers to a certain carbocyclic group or heterocyclic group.

  The term “O-carboxy” group refers to a —OC (═O) R ″ group, where R ″ is as defined herein.

  The term “C-carboxy” group refers to a —C (═O) OR ″ group, where R ″ is as defined herein.

  As used herein, the term “carboxylic acid” refers to a C-carboxy group where R ″ is hydro. In other words, the term “carboxylic acid” refers to —COOH.

  As used herein, the term “ester” is as defined above (eg, methyl, ethyl, or lower alkyl) except that R ″ is not hydro. C-carboxy group as defined in the specification.

As used herein, the term “C-carboxy salt” refers to a —C (═O) O ⁻ M ⁺ group, where M ⁺ is lithium, sodium, magnesium, calcium, potassium, Selected from the group consisting of barium, iron, zinc, and quaternary ammonium.

The term “carboxyalkyl” refers to —C _1-6 alkylene-C (═O) OR ″ (ie, an alkyl group is substituted with —C (═O) OR ″, and R ″ is defined herein. C _1-6 alkyl groups attached to the main structure as defined) Examples of carboxyalkyl include —CH ₂ COOH, — (CH ₂ ) ₂ COOH, — (CH ₂ ) ₃ COOH, - (CH _{2) 4} COOH, and - (CH _{2) 5} COOH include, but are not limited to.

  “Carboxyalkenyl” refers to -alkenylene-C (═O) OR ″, where R ″ is as defined herein.

The term “carboxyalkyl salt” refers to — (CH ₂ ) _r C (═O) O ⁻ M ⁺ , where M ⁺ is lithium, sodium, potassium, calcium, magnesium, barium, iron, zinc and the second. Selected from the group consisting of quaternary ammonium, and r is 1-6.

The term “carboxyalkoxy” refers to —O— (CH ₂ ) _r C (═O) OR ″, where r is 1 to 6 and R ″ is as defined herein. is there.

`` C _x carboxyalkanoyl '' means a carbonyl group (-(O =) C-) attached to an alkyl or cycloalkylalkyl group substituted with a carboxylic acid or carboxyalkyl group, where the carbon atom The total number of x is x (an integer of 2 or more).

`` C _x carboxyalkenoyl '' is a carbonyl group (-(O =) C-) bonded to an alkenyl group, alkyl group or cycloalkylalkyl group substituted with a carboxylic acid or carboxyalkyl group or carboxyalkenyl group. Where at least one double bond (—CH═CH—) is present and the total number of carbon atoms is x (an integer greater than or equal to 2).

“Carboxyalkoxyalkanoyl” means R ″ OC (═O) —C _1-6 alkylene-OC _1-6 alkylene-C (═O) —, where R ″ is defined herein. As defined.

“Amino” refers to the group —NR ^x R ^y , where R ^x and R ^y are as defined herein.

“Alkylamino” means an amino group wherein the substituent is C _1-6 alkyl.

  “Aminoalkyl” means an alkyl group attached to the main structure of a molecule that has a substituent wherein the alkyl group is amino.

“Quaternary ammonium” refers to the group − ⁺ N (R ^x ) (R ^y ) (R ^z ), where R ^x , R ^y , and R ^z are as defined herein. It is.

The term “nitro” refers to the —NO ₂ group.

The term “O-carbamyl” refers to the group —OC (═O) N (R ^x ) (R ^y ), where R ^x and R ^y are as defined herein.

The term “N-carbamyl” refers to the group R ^y OC (═O) N (R ^x ) —, where R ^x and R ^y are as defined herein.

The term “O-thiocarbamyl” refers to the group —OC (═S) N (R ^x ) (R ^y ), where R ^x and R ^y are as defined herein.

The term “N-thiocarbamyl” refers to the group R ^x OC (═S) NR ^y —, where R ^x and R ^y are as defined herein.

“C-amido” refers to the group —C (═O) N (R ^x ) (R ^y ), where R ^x and R ^y are as defined herein.

“N-amido” refers to the group R ^x C (═O) N (R ^y ) —, where R ^x and R ^y are as defined herein.

“Aminothiocarbonyl” refers to the group —C (═S) N (R ^x ) (R ^y ), where R ^x and R ^y are as defined herein.

“Hydroxyaminocarbonyl” means a —C (═O) N (R ^x ) (OH) group, where R ^x is as defined herein.

“Alkoxyaminocarbonyl” means a —C (═O) N (R ^x ) (alkoxy) group, where R ^x is as defined herein.

  The terms “cyano” and “cyanyl” refer to the group —C≡N.

  The term “nitrile” group, as used herein, refers to a —C≡N substituent.

  The term “cyanato” refers to a —CNO group.

  The term “isocyanato” refers to a —NCO group.

  The term “thiocyanato” refers to a —CNS group.

  The term “isothiocyanato” refers to a —NCS group.

  The term “oxo” refers to a —C (═O) — group.

  The term “sulfinyl” refers to the group —S (═O) R ″, where R ″ is as defined herein.

The term “sulfonyl” refers to a —S (═O) ₂ R ″ group, where R ″ is as defined herein.

The term “sulfonamido” refers to the group — (R ^x ) NS (═O) ₂ R ″, where R ″ and R ^x are as defined herein.

“Aminosulfonyl” means (R ^x ) (R ^y ) NS (═O) ₂ —, where R ^x and R ^y are as defined herein.

“Aminosulfonyloxy” means a group (R ^x ) (R ^y ) NS (═O) ₂ —O—, wherein R ^x and R ^y are as defined herein.

“Sulfonamidocarbonyl” means R ″ —S (═O) ₂ —N (R ^x ) —C (═O) —, where R ″ and R ^x are as defined herein. It is.

“Alkanoylaminosulfonyl” refers to an alkyl-C (═O) —N (R ^x ) —S (═O) ₂ — group, where R ^x is as defined herein.

The term “trihalomethylsulfonyl” refers to a X ₃ CS (═O) ₂ — group where X is halo.

The term “trihalomethylsulfonamido” refers to the group X ₃ CS (═O) ₂ N (R ^x ) —, where X is halo and R ^x is as defined herein. .

  R "is selected from the group consisting of hydro, alkyl, cycloalkyl, aryl, heteroaryl and heterocycle, each optionally substituted.

R ^x , R ^y , and R ^z are independently selected from the group consisting of hydro and optionally substituted alkyl.

The term “methylenedioxy” refers to an —OCH ₂ O— group in which an oxygen atom is bonded to an adjacent ring carbon atom.

The term “ethylenedioxy” refers to the group —OCH ₂ CH ₂ O—, in which an oxygen atom is bonded to an adjacent ring carbon atom.

  As used herein, the phrase “optionally substituted” means substituted or unsubstituted.

  Unless stated otherwise explicitly or indicated by a linking group number (dash, double dash or triple dash), the point of attachment to the group described is in the group described to the far right. Thus, for example, a hydroxyalkyl group is attached to the main structure through the alkyl, and the hydroxyl is a substituent on the alkyl.

2. Therapeutic compounds The present invention provides compounds that selectively inhibit the activity of Nampt. These compounds treat cancer, systemic or chronic inflammation, rheumatoid arthritis, diabetes, obesity, T cell-mediated autoimmune diseases, ischemia, and other complications associated with these diseases and disorders Can be used.

  Specifically, the present invention provides compounds of formula I

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式Iにおいて:
Yは、フェニル、2-ピリジニル、3-ピリジニル、または4-ピリジニルであり、ここで任意の環炭素は独立して、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、またはスルフィニルで必要に応じて置換されており;
Y₁は、二価の炭素環、二価の複素環、二価のフェニルまたは二価のヘテロアリールであり、ここで任意の環原子は独立して、ハロ、C_1〜5アルキル、ニトロ、シアノ、トリハロメチル、C_1〜5アルコキシ、C-アミド、N-アミド、スルホンアミド、アミノ、アミノスルホニル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、またはスルフィニルで必要に応じて置換されているか、あるいは
Y₁は、C_2〜8アルキレンまたはC_2〜8アルケニレンであり、必要に応じて、-O-、-S-、-S(=O)-、-S(=O)₂-、-OC(=O)N(R)-、-N(R)C(=O)O-、-C(=O)N(R)-、-N(R)C(=O)-、-N(R)C(=O)N(R)-、-N(R)-、-C(=O)-、-OC(=O)-、-C(=O)O-、-OS(=O)₂N(R)-、-N(R)S(=O)₂O-、-SC(=O)-、-C(=O)S-、-OC(=S)N(R)-、-N(R)C(=S)O-、-C(=S)N(R)-、-N(R)C(=S)-、-N(R)C(=S)N(R)-、-C(=S)-、-OC(=S)-、-C(=S)O-、-S(=O)₂N(R)-、-N(R)S(=O)₂-、-S(=O)₂N(R)C(=O)-、または-C(=O)N(R)S(=O)₂-により１回、２回、または３回介在されており;
Y₂は、-OCH₂-、-SCH₂-、-N(R)CH₂-、-N(R)C(=O)-、-C(=O)N(R)-、-S(=O)₂CH₂-、-S(=O)CH₂-、-CH₂O-、-CH₂CH₂O-、-CH₂S-、-CH₂N(R)-、-CH₂S(=O)₂-、-CH₂S(=O)-、-C(=O)O-、-OC(=O)-、-SO₂N(R)-、-N(R)SO₂-、エチレン、プロピレン、n-ブチレン、-O-C_1〜4アルキレン-N(R)C(=O)-、-O-C_1〜4アルキレン-C(=O)N(R)-、-N(R)C(=O)-C_1〜4アルキレン-O-、-C(=O)N(R)-C_1〜4アルキレン-O-、-C_1〜4アルキレン-S(=O)₂-、-C_1〜4アルキレン-S(=O)-、-S(=O)₂-C_1〜4アルキレン-、-S(=O)-C_1〜4アルキレン-、-C_1〜4アルキレン-SO₂N(R)-、-C_1〜4アルキレン-N(R)SO₂-、-SO₂N(R)-C_1〜4アルキレン-、-N(R)SO₂-C_1〜4アルキレン-、-C_1〜4アルキレン-O-C_1〜4アルキレン-、-O-C_1〜4アルキレン-、-C_1〜4アルキレン-O-、-S-C_1〜4アルキレン-、-C_1〜4アルキレン-S-、-C_1〜4アルキレン-S-C_1〜4アルキレン-、-N(R)-C_1〜4アルキレン-、-C_1〜4アルキレン-N(R)-、-C_1〜4アルキレン-N(R)-C_1〜4アルキレン-、-C_1〜4アルキレン-C(=O)-O-C_1〜4アルキレン-、-C_1〜4アルキレン-O-C(=O)-C_1〜4アルキレン-、-C_1〜4アルキレン-C(=O)-N(R)-C_1〜4アルキレン-、-C_1〜4アルキレン-N(R)-C(=O)-C_1〜4アルキレン-、-C(=O)-N(R)-C_1〜4アルキレン-SO₂N(R)-、または-N(R)-C(=O)-C_1〜4アルキレン-SO₂N(R)-であり;
Z₀は、炭素環、シクロアルキル、シクロアルケニル、複素環、ヘテロシクロノイル、アリール、ヘテロアリール、カルボシクロアルキル、ヘテロシクリルアルキル、アリールアルキル、アリールアルケニル、ヘテロアリールアルキル、ヘテロアリールアルケニル、ヘテロアリールアルキニル、またはアリールアルキニルであり、ここで上記基のうちの任意のものは、必要に応じて、アルキル、アルキレン、アルケニル、アルケニレン、アルキニル、アルキニレン、炭素環、シクロアルキル、シクロアルケニル、複素環、アリール、ヘテロアリール、ハロ、ヒドロ、ヒドロキシル、アルコキシ、アルキニルオキシ、シクロアルキルオキシ、ヘテロシクロオキシ、アリールオキシ、ヘテロアリールオキシ、アリールアルコキシ、ヘテロアリールアルコキシ、メルカプト、アルキルチオ、アリールチオ、アリールアルキル、ヘテロアリールアルキル、ヘテロアリールアルケニル、アリールアルキニル、ハロアルキル、アルデヒド、チオカルボニル、ヘテロシクロノイル、O-カルボキシ、C-カルボキシ、カルボン酸、エステル、C-カルボキシ塩、カルボキシアルキル、カルボキシアルケニレン、カルボキシアルキル塩、カルボキシアルコキシ、カルボキシアルコキシアルカノイル、アミノ、アミノアルキル、ニトロ、O-カルバミル、N-カルバミル、O-チオカルバミル、N-チオカルバミル、C-アミド、N-アミド、アミノチオカルボニル、ヒドロキシアミノカルボニル、アルコキシアミノカルボニル、シアノ、ニトリル、シアナト、イソシアナト、チオシアナト、イソチオシアナト、スルフィニル、スルホニル、スルホンアミド、アミノスルホニル、アミノスルホニルオキシ、スルホンアミドカルボニル、アルカノイルアミノスルホニル、トリハロメチルスルホニル、またはトリハロメチルスルホンアミドで少なくとも１回置換されており;
ここで任意のアルキレン基またはアルケニレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
ここでYおよびY₁においては、Rは、H、ハロ、C_1〜4アルキル、C_1〜4アルケニル、またはC_1〜4アルキニルであり;
ここでY₂においては、Rは、H、ハロ、C_1〜5アルキル、C_1〜5アルケニル、C_1〜5アルキニルであるか、またはZ₀の炭素原子と一緒に複素環を形成し;そして
ただし、この化合物は:
3-(ピリジン-3-イル)-4-({4-[(3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}ベンジル)オキシ]フェニル}スルホニル)ブタン酸エチル;
4-({4-[(3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}ベンジル)オキシ]フェニル}スルホニル)-3-[4-(トリフルオロメチル)フェニル]ブタン酸;
3-フェニル-4-({4-[(3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}ベンジル)オキシ]フェニル}スルホニル)ブタン酸;
3-(4-クロロ-3-フルオロフェニル)-4-[(4-{[3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}-5-(トリフルオロメチル)ベンジル]オキシ}フェニル)スルホニル]ブタン酸;
3-フェニル-4-[(4-{[3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}-5-(トリフルオロメチル)ベンジル]オキシ}フェニル)スルホニル]ブタン酸;
3-(ピリジン-3-イル)-4-({4-[(3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}ベンジル)オキシ]フェニル}スルホニル)ブタン酸;
4-({4-[(4-フルオロ-3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}ベンジル)オキシ]フェニル}スルホニル)-3-(ピリジン-3-イル)ブタン酸;
1,1'-ブタン-1,4-ジイルビス[3-(ピリジン-3-イルメチル)尿素];
1-[(6-メトキシピリジン-3-イル)メチル]-3-[3-(3-メチルフェノキシ)プロピル]尿素;または
1-[3-(2-フルオロフェノキシ)プロピル]-3-[(6-メトキシピリジン-3-イル)メチル]尿素
ではない。

And the pharmaceutically acceptable salts and solvates thereof, in Formula I:
Y is phenyl, 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl, where any ring carbon is independently halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C Optionally substituted with -amide, N-amide, C-carboxy, O-carboxy, sulfonamido, amino, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl;
Y ₁ is a divalent carbocycle, divalent heterocycle, divalent phenyl or divalent heteroaryl, wherein any ring atom is independently halo, C _1-5 alkyl, nitro, Optionally substituted with cyano, trihalomethyl, C _1-5 alkoxy, C-amide, N-amide, sulfonamido, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl, or
Y ₁ is C _2-8 alkylene or C _2-8 alkenylene, and optionally -O-, -S-, -S (= O)-, -S (= O) _2- , -OC (= O) N (R)-, -N (R) C (= O) O-, -C (= O) N (R)-, -N (R) C (= O)-, -N ( R) C (= O) N (R)-, -N (R)-, -C (= O)-, -OC (= O)-, -C (= O) O-, -OS (= O ) ₂ N (R)-, -N (R) S (= O) ₂ O-, -SC (= O)-, -C (= O) S-, -OC (= S) N (R)- , -N (R) C (= S) O-, -C (= S) N (R)-, -N (R) C (= S)-, -N (R) C (= S) N ( R)-, -C (= S)-, -OC (= S)-, -C (= S) O-, -S (= O) ₂ N (R)-, -N (R) S (= O) _2- , -S (= O) ₂ N (R) C (= O)-, or -C (= O) N (R) S (= O) _2- once, twice, or 3 Intervening times;
Y _{2 is, -OCH 2 -, - SCH 2} -, - N (R) CH 2 -, - N (R) C (= O) -, - C (= O) N (R) -, - S ( = O) ₂ CH _2- , -S (= O) CH _2- , -CH ₂ O-, -CH ₂ CH ₂ O-, -CH ₂ S-, -CH ₂ N (R)-, -CH ₂ S (= O) _2- , -CH ₂ S (= O)-, -C (= O) O-, -OC (= O)-, -SO ₂ N (R)-, -N (R) SO _2- , ethylene, propylene, n-butylene, -OC _1-4 alkylene-N (R) C (= O)-, -OC _1-4 alkylene-C (= O) N (R)-, -N ( R) C (= O) -C _1-4 alkylene-O-, -C (= O) N (R) -C _1-4 alkylene-O-, -C _1-4 alkylene-S (= O) ₂ -, -C _1-4 alkylene-S (= O)-, -S (= O) ₂ -C _1-4 alkylene-, -S (= O) -C _1-4 alkylene-, -C _1-4 alkylene _{-SO 2 N (R) -,} - C 1~4 alkylene _{-N (R) SO 2 -,} - SO 2 N (R) -C 1~4 alkylene -, - N (R) SO 2 -C 1 _{to 4} alkylene -, - C _{1 to 4} alkylene -OC _{1 to 4} alkylene -, - OC _{1 to 4} alkylene -, - C _{1 to 4} alkylene -O _-, - SC _1~4 alkylene -, - C _{1 to 4} alkylene -S _-, - C _1~4 alkylene -SC _{1 to 4} alkylene -, - N (R) -C 1~4 alkylene -, - C _{1 to 4} alkylene -N (R) -, - C 1~4 alkylene -N (R) -C _1~4 alkylene -, - C _{1 to 4} alkylene -C (= O) -OC _1~4 alkylene _-, - C 1~ ₄ alkylene-OC (= O) -C _1-4 alkylene-, -C _1-4 alkylene-C (= O) -N (R) -C _1-4 alkylene-, -C _1-4 alkylene-N ( R) -C (= O) -C _1-4 alkylene-, -C (= O) -N (R) -C _1-4 alkylene-SO ₂ N (R)-, or -N (R) -C (= O) -C _1-4 alkylene-SO ₂ N (R)-;
Z ₀ is carbocycle, cycloalkyl, cycloalkenyl, heterocycle, heterocyclonoyl, aryl, heteroaryl, carbocycloalkyl, heterocyclylalkyl, arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, Or arylalkynyl, wherein any of the above groups are optionally alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, carbocycle, cycloalkyl, cycloalkenyl, heterocycle, aryl, hetero Aryl, halo, hydro, hydroxyl, alkoxy, alkynyloxy, cycloalkyloxy, heterocyclooxy, aryloxy, heteroaryloxy, arylalkoxy, heteroaryl Koxy, mercapto, alkylthio, arylthio, arylalkyl, heteroarylalkyl, heteroarylalkenyl, arylalkynyl, haloalkyl, aldehyde, thiocarbonyl, heterocyclonoyl, O-carboxy, C-carboxy, carboxylic acid, ester, C-carboxy salt , Carboxyalkyl, carboxyalkenylene, carboxyalkyl salt, carboxyalkoxy, carboxyalkoxyalkanoyl, amino, aminoalkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amide, N-amide, amino Thiocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, cyano, nitrile, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, Honiru, sulfonamido, aminosulfonyl, amino sulfonyloxy, sulfonamido carbonyl, alkanoylamino sulfonyl is substituted at least once with a trihalomethyl sulfonyl or trihalomethyl sulfonamide;
Where any alkylene or alkenylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
Where in Y and Y ₁ , R is H, halo, C _1-4 alkyl, C _1-4 alkenyl, or C _1-4 alkynyl;
Where in Y ₂ R is H, halo, C _1-5 alkyl, C _1-5 alkenyl, C _1-5 alkynyl, or forms a heterocycle with the carbon atom of Z ₀ ; And this compound:
3- (pyridin-3-yl) -4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) butanoic acid ethyl;
4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) -3- [4- (trifluoromethyl) phenyl] butanoic acid;
3-phenyl-4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) butanoic acid;
3- (4-Chloro-3-fluorophenyl) -4-[(4-{[3-{[(pyridin-3-ylmethyl) carbamoyl] amino} -5- (trifluoromethyl) benzyl] oxy} phenyl) Sulfonyl] butanoic acid;
3-phenyl-4-[(4-{[3-{[(pyridin-3-ylmethyl) carbamoyl] amino} -5- (trifluoromethyl) benzyl] oxy} phenyl) sulfonyl] butanoic acid;
3- (pyridin-3-yl) -4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) butanoic acid;
4-({4-[(4-Fluoro-3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) -3- (pyridin-3-yl) butanoic acid;
1,1'-butane-1,4-diylbis [3- (pyridin-3-ylmethyl) urea];
1-[(6-methoxypyridin-3-yl) methyl] -3- [3- (3-methylphenoxy) propyl] urea; or
It is not 1- [3- (2-fluorophenoxy) propyl] -3-[(6-methoxypyridin-3-yl) methyl] urea.

  In some embodiments, the present invention provides compounds of formula Ia

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式Iaにおいて:
Z₀およびY₂は、上記式Iについて定義されたとおりであり;
nは、3、4、5、6、または7であり;
任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₇は、１回以上存在する場合、ピリジニル環上の水素原子を置き換え、そしてハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから独立して選択され;そして
ただし、この化合物は:
1,1'-ブタン-1,4-ジイルビス[3-(ピリジン-3-イルメチル)尿素]
ではない。

And the pharmaceutically acceptable salts and solvates thereof, in Formula Ia:
Z ₀ and Y ₂ are as defined for formula I above;
n is 3, 4, 5, 6, or 7;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₇ when present more than once replaces a hydrogen atom on the pyridinyl ring and is halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, Independently selected from C-carboxy, O-carboxy, trihalomethyl, C-carboxy, O-carboxy, sulfonamido, amino, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl;
1,1'-butane-1,4-diylbis [3- (pyridin-3-ylmethyl) urea]
is not.

  In some embodiments, the present invention provides compounds of formula Ia1

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式Ia1において:
Z₀は、上記式Iについて定義されたとおりであり;
nは、3、4、5、6、または7であり;
任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;そして
R₇は、式Iaについて定義されたとおりである。

And a pharmaceutically acceptable salt and solvate thereof, in Formula Ia1:
Z ₀ is as defined above for formula I;
n is 3, 4, 5, 6, or 7;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl; and
R ₇ is as defined for formula Ia.

  In some embodiments, the present invention provides compounds of formula Ia2

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式Ia2において:
Z₀は、上記式Iについて定義されたとおりであり;
nは、3、4、5、6、または7であり;
任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₂は、H、C_1〜55アルキル、C_1〜55アルケニル、またはC_1〜5アルキニルであり;そして
R₇は、式Iaについて定義されたとおりである。

And a pharmaceutically acceptable salt and solvate thereof, in Formula Ia2:
Z ₀ is as defined above for formula I;
n is 3, 4, 5, 6, or 7;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₂ is H, C _1-55 alkyl, C _1-55 alkenyl, or C _1-5 alkynyl; and
R ₇ is as defined for formula Ia.

  In some embodiments, the present invention provides compounds of formula Ib

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式Ibにおいて:
Z₀およびY₂は、上記式Iについて定義されたとおりであり;
任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₆およびR₇は各々独立して、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから選択され;そして
S、T、U、およびVは、炭素または窒素であり、ただし、S、T、U、またはVが窒素である場合、この窒素上に置換基は存在しない。

And the pharmaceutically acceptable salts and solvates thereof, in Formula Ib:
Z ₀ and Y ₂ are as defined for formula I above;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₆ and R ₇ are each independently halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide Selected from, amino, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl; and
S, T, U, and V are carbon or nitrogen, provided that when S, T, U, or V is nitrogen, there are no substituents on the nitrogen.

  In some embodiments, the present invention provides compounds of formula Ib1

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式Ib1において:
Z₀は、上記式Iについて定義されたとおりであり;
任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₃およびR₄は各々独立して、HまたはC_1〜4アルキルであるか、あるいはR₃およびR₄は、これらが結合している炭素と一緒になって、シクロプロピル環またはシクロブチル環を形成し;そして
R₆およびR₇は、上記式Ibについて定義された領域である。

And the pharmaceutically acceptable salts and solvates thereof, in Formula Ib1:
Z ₀ is as defined above for formula I;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₃ and R ₄ are each independently H or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which they are attached form a cyclopropyl or cyclobutyl ring. Forming; and
R ₆ and R ₇ are the regions defined for formula Ib above.

  In some embodiments, the present invention provides compounds of formula Ib2

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式Ib2において:
Z₀は、上記式Iについて定義されたとおりであり;
任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₂は、H、C_1〜5アルキル、C_1〜5アルケニル、またはC_1〜5アルキニルであり;そして
R₆およびR₇は、上記式Ibについて定義されたとおりである。

And the pharmaceutically acceptable salts and solvates thereof, in Formula Ib2:
Z ₀ is as defined above for formula I;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₂ is H, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl; and
R ₆ and R ₇ are as defined for formula Ib above.

  In some embodiments, the present invention provides compounds of formula Ib3

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式Ib3において:
Z₀は、上記式Iについて定義されたとおりであり;
uは、0または1であり;
任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;そして
R₆およびR₇は、上記式Ibについて定義されたとおりである。

And the pharmaceutically acceptable salts and solvates thereof, in Formula Ib3:
Z ₀ is as defined above for formula I;
u is 0 or 1;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl; and
R ₆ and R ₇ are as defined for formula Ib above.

  In some embodiments, the present invention provides compounds of formula Ic

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式Icにおいて:
Z₀およびY₁は、上記式Iについて定義されたとおりであり;
任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₃およびR₄は各々独立して、HまたはC_1〜4アルキルであるか、あるいはR₃およびR₄は、これらが結合している炭素と一緒になって、シクロプロピル環またはシクロブチル環を形成し;
R₇は、１回以上存在する場合、ピリジニル環上の水素原子を置き換え、そしてハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから独立して選択され;そして
ただし、この化合物は:
3-(ピリジン-3-イル)-4-({4-[(3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}ベンジル)オキシ]フェニル}スルホニル)ブタン酸エチル;
4-({4-[(3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}ベンジル)オキシ]フェニル}スルホニル)-3-[4-(トリフルオロメチル)フェニル]ブタン酸;
3-フェニル-4-({4-[(3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}ベンジル)オキシ]フェニル}スルホニル)ブタン酸;
3-(4-クロロ-3-フルオロフェニル)-4-[(4-{[3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}-5-(トリフルオロメチル)ベンジル]オキシ}フェニル)スルホニル]ブタン酸;
3-フェニル-4-[(4-{[3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}-5-(トリフルオロメチル)ベンジル]オキシ}フェニル)スルホニル]ブタン酸;
3-(ピリジン-3-イル)-4-({4-[(3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}ベンジル)オキシ]フェニル}スルホニル)ブタン酸;または
4-({4-[(4-フルオロ-3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}ベンジル)オキシ]フェニル}スルホニル)-3-(ピリジン-3-イル)ブタン酸
ではない。

And the pharmaceutically acceptable salts and solvates thereof, in Formula Ic:
Z ₀ and Y ₁ are as defined for formula I above;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₃ and R ₄ are each independently H or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which they are attached form a cyclopropyl or cyclobutyl ring. Forming;
R ₇ when present more than once replaces a hydrogen atom on the pyridinyl ring and is halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, Independently selected from C-carboxy, O-carboxy, sulfonamido, amino, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl; and the compound is:
3- (pyridin-3-yl) -4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) butanoic acid ethyl;
4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) -3- [4- (trifluoromethyl) phenyl] butanoic acid;
3-phenyl-4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) butanoic acid;
3- (4-Chloro-3-fluorophenyl) -4-[(4-{[3-{[(pyridin-3-ylmethyl) carbamoyl] amino} -5- (trifluoromethyl) benzyl] oxy} phenyl) Sulfonyl] butanoic acid;
3-phenyl-4-[(4-{[3-{[(pyridin-3-ylmethyl) carbamoyl] amino} -5- (trifluoromethyl) benzyl] oxy} phenyl) sulfonyl] butanoic acid;
3- (pyridin-3-yl) -4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) butanoic acid; or
4-({4-[(4-Fluoro-3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) -3- (pyridin-3-yl) butanoic acid.

  In some embodiments, the present invention provides compounds of formula Id

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式Idにおいて:
Z₀およびY₁は、上記式Iについて定義されたとおりであり;
任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₂は、H、C_1〜5アルキル、C_1〜5アルケニル、またはC_1〜5アルキニルであり;そして
R₇は、１回以上存在する場合、ピリジニル環上の水素原子を置き換え、そしてハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから独立して選択される。

And the pharmaceutically acceptable salts and solvates thereof, in formula Id:
Z ₀ and Y ₁ are as defined for formula I above;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₂ is H, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl; and
R ₇ when present more than once replaces a hydrogen atom on the pyridinyl ring and is halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, Independently selected from C-carboxy, O-carboxy, sulfonamido, amino, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl.

  The present invention further provides Formula II

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIにおいて:
Zは、ヒドロ、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、またはスルフィニルであり、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されているか;
あるいはZは、上記式Iについて定義されたようなZ₀であり;
YおよびY₁ Rは、上記式Iについて定義されたとおりであり、ここでY₂においては、Rは、H、C_1〜5アルキル、C_1〜5アルケニル、C_1〜5アルキニルであるか、またはY₃の炭素原子と一緒に複素環を形成し;
Y₃は、アリールまたはヘテロアリールであり、ここで任意の環炭素は独立して、ハロ、C_1〜5アルキル、ニトロ、シアノ、トリハロメチル、C_1〜5アルコキシ、C-アミド、N-アミド、スルホンアミド、アミノ、アミノスルホニル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、またはスルフィニルで必要に応じて置換されており、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;
任意のアルキレン基またはアルケニレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;そして
ただし、この化合物は:
1-[(6-メトキシピリジン-3-イル)メチル]-3-[3-(3-メチルフェノキシ)プロピル]尿素;
1-[3-(2-フルオロフェノキシ)プロピル]-3-[(6-メトキシピリジン-3-イル)メチル]尿素;
3-(ピリジン-3-イル)-4-({4-[(3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}ベンジル)オキシ]フェニル}スルホニル)ブタン酸エチル;
4-({4-[(3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}ベンジル)オキシ]フェニル}スルホニル)-3-[4-(トリフルオロメチル)フェニル]ブタン酸;
3-フェニル-4-({4-[(3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}ベンジル)オキシ]フェニル}スルホニル)ブタン酸;
3-(4-クロロ-3-フルオロフェニル)-4-[(4-{[3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}-5-(トリフルオロメチル)ベンジル]オキシ}フェニル)スルホニル]ブタン酸;
3-フェニル-4-[(4-{[3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}-5-(トリフルオロメチル)ベンジル]オキシ}フェニル)スルホニル]ブタン酸;
3-(ピリジン-3-イル)-4-({4-[(3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}ベンジル)オキシ]フェニル}スルホニル)ブタン酸;または
4-({4-[(4-フルオロ-3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}ベンジル)オキシ]フェニル}スルホニル)-3-(ピリジン-3-イル)ブタン酸
ではない。

And a pharmaceutically acceptable salt and solvate thereof, in Formula II:
Z is hydro, halo, _C1-5 alkyl, nitro, cyano, _C1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, trihalomethyl, C-carboxy, O -Carboxy, sulfonamido, amino, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl, where _C1-5 alkyl, _C1-5 alkoxy, C-amide, N-amido, amino, and alkylthio are each Optionally substituted with heterocyclo, cycloalkyl, or amino;
Or Z is Z ₀ as defined above for formula I;
Y and Y ₁ R are as defined above for formula I, wherein in Y ₂ is R R H, C _1-5 alkyl, C _1-5 alkenyl, C _1-5 alkynyl , Or together with the carbon atom of Y ₃ forms a heterocyclic ring;
Y ₃ is aryl or heteroaryl, wherein any ring carbon is independently halo, C _1-5 alkyl, nitro, cyano, trihalomethyl, C _1-5 alkoxy, C-amide, N-amide , Sulfonamide, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl, optionally substituted, where C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide , Amino, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
Any alkylene or alkenylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl; and provided that the compound is :
1-[(6-methoxypyridin-3-yl) methyl] -3- [3- (3-methylphenoxy) propyl] urea;
1- [3- (2-fluorophenoxy) propyl] -3-[(6-methoxypyridin-3-yl) methyl] urea;
3- (pyridin-3-yl) -4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) butanoic acid ethyl;
4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) -3- [4- (trifluoromethyl) phenyl] butanoic acid;
3-phenyl-4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) butanoic acid;
3- (4-Chloro-3-fluorophenyl) -4-[(4-{[3-{[(pyridin-3-ylmethyl) carbamoyl] amino} -5- (trifluoromethyl) benzyl] oxy} phenyl) Sulfonyl] butanoic acid;
3-phenyl-4-[(4-{[3-{[(pyridin-3-ylmethyl) carbamoyl] amino} -5- (trifluoromethyl) benzyl] oxy} phenyl) sulfonyl] butanoic acid;
3- (pyridin-3-yl) -4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) butanoic acid; or
4-({4-[(4-Fluoro-3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) -3- (pyridin-3-yl) butanoic acid.

  In some embodiments, the present invention provides compounds of formula IIa

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIaにおいて：
Z、Y₂、およびY₃は、上記式IIについて定義されたとおりであり;
nは、3、4、5、6、または7であり;
任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;そして
R₇は、１回以上存在する場合、ピリジニル環上の水素原子を置き換え、そしてハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから独立して選択される。

And the pharmaceutically acceptable salts and solvates thereof, in Formula IIa:
Z, Y ₂ and Y ₃ are as defined for Formula II above;
n is 3, 4, 5, 6, or 7;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl; and
R ₇ when present more than once replaces a hydrogen atom on the pyridinyl ring and is halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, Independently selected from C-carboxy, O-carboxy, sulfonamido, amino, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl.

  In some embodiments, the present invention provides compounds of formula IIa1

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIa1において:
ZおよびY₃は、上記式IIについて定義されたとおりであり;
nは、3、4、5、6、または7であり;
任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;そして
R₇は、上記式IIaについて定義されたとおりである。

And the pharmaceutically acceptable salts and solvates thereof, in Formula IIa1:
Z and Y ₃ are as defined for Formula II above;
n is 3, 4, 5, 6, or 7;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl; and
R ₇ is as defined for Formula IIa above.

  In some embodiments, the present invention provides compounds of formula IIa2

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIa2において:
ZおよびY₃は、上記式IIについて定義されたとおりであり;
nは、3、4、5、6、または7であり;
任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₂は、H、C_1〜5アルキル、C_1〜5アルケニル、またはC_1〜5アルキニルであり;そして
R₇は、上記式IIaについて定義されたとおりである。

And a pharmaceutically acceptable salt and solvate thereof, in Formula IIa2:
Z and Y ₃ are as defined for Formula II above;
n is 3, 4, 5, 6, or 7;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₂ is H, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl; and
R ₇ is as defined for Formula IIa above.

  In some embodiments, the present invention provides compounds of formula IIa3

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIa3において:
Zは、上記式IIについて定義されたとおりであり;
nは、3、4、5、6、または7であり;
任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₁は、１回以上存在する場合、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、アミノアルキル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから独立して選択され、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、アミノアルキル、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;そして
R₇は、上記式IIaについて定義されたとおりである。

And a pharmaceutically acceptable salt and solvate thereof, in Formula IIa3:
Z is as defined for Formula II above;
n is 3, 4, 5, 6, or 7;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino; and
R ₇ is as defined for Formula IIa above.

  In some embodiments, the present invention provides compounds of formula IIa4

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIa4において:
Zは、上記式IIについて定義されたとおりであり;
nは、3、4、5、6、または7であり;
任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₁は、１回以上存在する場合、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、アミノアルキル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから独立して選択され、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、アミノアルキル、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;
R₂は、H、C_1〜5アルキル、C_1〜5アルケニル、またはC_1〜5アルキニルであり;そして
R₇は、上記式IIaについて定義されたとおりである。

And a pharmaceutically acceptable salt and solvate thereof, in Formula IIa4:
Z is as defined for Formula II above;
n is 3, 4, 5, 6, or 7;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₂ is H, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl; and
R ₇ is as defined for Formula IIa above.

  In some embodiments, the present invention provides compounds of formula IIb

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIbにおいて:
Z、Y₂、およびY₃は、上記式IIについて定義されたとおりであり、
任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₆およびR₇は各々独立して、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから選択され;そして
S、T、U、およびVは、炭素または窒素であり、ただし、S、T、U、またはVが窒素である場合、この窒素上に置換基は存在しない。

And the pharmaceutically acceptable salts and solvates thereof, in Formula IIb:
Z, Y ₂ and Y ₃ are as defined for Formula II above,
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₆ and R ₇ are each independently halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide Selected from, amino, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl; and
S, T, U, and V are carbon or nitrogen, provided that when S, T, U, or V is nitrogen, there are no substituents on the nitrogen.

  In some embodiments, the present invention provides compounds of formula IIb1

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIb1において:
ZおよびY₃は、上記式IIについて定義されたとおりであり、
任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₃およびR₄は各々独立して、HまたはC_1〜4アルキルであるか、あるいはR₃およびR₄は、これらが結合している炭素と一緒になって、シクロプロピル環またはシクロブチル環を形成し;そして
R₆およびR₇は、上記式IIbについて定義されたとおりである。

And a pharmaceutically acceptable salt and solvate thereof, in Formula IIb1:
Z and Y ₃ are as defined for Formula II above,
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₃ and R ₄ are each independently H or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which they are attached form a cyclopropyl or cyclobutyl ring. Forming; and
R ₆ and R ₇ are as defined for Formula IIb above.

  In some embodiments, the present invention provides compounds of formula IIb2

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIb2において:
ZおよびY₃は、上記式IIについて定義されたとおりであり;
任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₂は、H、C_1〜5アルキル、C_1〜5アルケニル、またはC_1〜5アルキニルであり;そして
R₆およびR₇は、上記式IIbについて定義されたとおりである。

And a pharmaceutically acceptable salt and solvate thereof, in Formula IIb2:
Z and Y ₃ are as defined for Formula II above;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₂ is H, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl; and
R ₆ and R ₇ are as defined for Formula IIb above.

  In some embodiments, the present invention provides compounds of formula IIb3

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIb3において:
ZおよびY₃は、上記式IIについて定義されたとおりであり、
uは、0または1であり;
任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;そして
R₆およびR₇は、上記式IIbについて定義されたとおりである。

And a pharmaceutically acceptable salt and solvate thereof, in Formula IIb3:
Z and Y ₃ are as defined for Formula II above,
u is 0 or 1;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl; and
R ₆ and R ₇ are as defined for Formula IIb above.

  In some embodiments, the present invention provides compounds of formula IIb4

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIb4において:
Zは、上記式IIについて定義されたとおりであり;
任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₁は、１回以上存在する場合、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、アミノアルキル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから独立して選択され、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、アミノアルキル、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;
R₃およびR₄は各々独立して、HまたはC_1〜4アルキルであるか、あるいはR₃およびR₄は、これらが結合している炭素と一緒になって、シクロプロピル環またはシクロブチル環を形成し;そして
R₆およびR₇は、上記式IIbについて定義されたとおりである。

And a pharmaceutically acceptable salt and solvate thereof, in Formula IIb4:
Z is as defined for Formula II above;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₃ and R ₄ are each independently H or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which they are attached form a cyclopropyl or cyclobutyl ring. Forming; and
R ₆ and R ₇ are as defined for Formula IIb above.

  In some embodiments, the present invention provides compounds of formula IIb5

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIb5において:
Zは、上記式IIについて定義されたとおりであり;
任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₁は、１回以上存在する場合、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、アミノアルキル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから独立して選択され、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、アミノアルキル、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;
R₂は、H、C_1〜5アルキル、C_1〜5アルケニル、またはC_1〜5アルキニルであり;そして
R₆およびR₇は、上記式IIbについて定義されたとおりである。

And a pharmaceutically acceptable salt and solvate thereof, in Formula IIb5:
Z is as defined for Formula II above;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₂ is H, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl; and
R ₆ and R ₇ are as defined for Formula IIb above.

  In some embodiments, the present invention provides compounds of formula IIb6

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIb6において:
Zは、上記式IIについて定義されたとおりであり;
uは、0または1であり;
任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₁は、１回以上存在する場合、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、アミノアルキル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから独立して選択され、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、アミノアルキル、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;そして
R₆およびR₇は、上記式IIbについて定義されたとおりである。

And a pharmaceutically acceptable salt and solvate thereof, in Formula IIb6:
Z is as defined for Formula II above;
u is 0 or 1;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino; and
R ₆ and R ₇ are as defined for Formula IIb above.

  In some embodiments, the present invention provides compounds of formula IIb7

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIb7において:
ZおよびY₂は、上記式IIについて定義されたとおりであり;
任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₁は、１回以上存在する場合、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、アミノアルキル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから独立して選択され、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、アミノアルキル、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;そして
R₆およびR₇は、上記式IIbについて定義されたとおりである。

And a pharmaceutically acceptable salt and solvate thereof, in Formula IIb7:
Z and Y ₂ are as defined for Formula II above;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino; and
R ₆ and R ₇ are as defined for Formula IIb above.

  In some embodiments, the present invention provides compounds of formula IIc

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIcにおいて:
Z、Y₁、およびY₃は、上記式IIについて定義されたとおりであり;
任意のアルキレン基またはアルケニレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₃およびR₄は各々独立して、HまたはC_1〜4アルキルであるか、あるいはR₃およびR₄は、これらが結合している炭素と一緒になって、シクロプロピル環またはシクロブチル環を形成し;そして
R₇は、１回以上存在する場合、ピリジニル環上の水素原子を置き換え、そしてハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから独立して選択される。

And the pharmaceutically acceptable salts and solvates thereof, in Formula IIc:
Z, Y ₁ and Y ₃ are as defined for Formula II above;
Any alkylene or alkenylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₃ and R ₄ are each independently H or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which they are attached form a cyclopropyl or cyclobutyl ring. Forming; and
R ₇ when present more than once replaces a hydrogen atom on the pyridinyl ring and is halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, Independently selected from C-carboxy, O-carboxy, sulfonamido, amino, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl.

  In some embodiments, the present invention provides compounds of formula IIc1

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIc1において:
ZおよびY₁は、上記式IIにおいて定義されたとおりであり;
任意のアルキレン基またはアルケニレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₁は、１回以上存在する場合、ハロ、C_1〜5アルキル、ニトロ、シアノ、アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、アミノアルキル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから独立して選択され、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、アミノアルキル、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;そして
R₃、R₄、およびR₇は、式IIcについて定義されたとおりである。

And a pharmaceutically acceptable salt and solvate thereof, in Formula IIc1:
Z and Y ₁ are as defined in Formula II above;
Any alkylene or alkenylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₁ is halo, C _1-5 alkyl, nitro, cyano, alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide, amino, amino when present more than once Independently selected from alkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, and alkylthio are Each optionally substituted with heterocyclo, cycloalkyl, or amino; and
R ₃ , R ₄ , and R ₇ are as defined for Formula IIc.

  In some embodiments, the present invention provides compounds of formula IId

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIdにおいて:
Z、Y₁、およびY₃は、上記式IIについて定義されたとおりであり;
任意のアルキレン基またはアルケニレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₂は、H、C_1〜5アルキル、C_1〜5アルケニル、またはC_1〜5アルキニルであり;そして
R₇は、１回以上存在する場合、ピリジニル環上の水素原子を置き換え、そしてハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから独立して選択される。

And the pharmaceutically acceptable salts and solvates thereof, in Formula IId:
Z, Y ₁ and Y ₃ are as defined for Formula II above;
Any alkylene or alkenylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₂ is H, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl; and
R ₇ when present more than once replaces a hydrogen atom on the pyridinyl ring and is halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, Independently selected from C-carboxy, O-carboxy, sulfonamido, amino, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl.

  In some embodiments, the present invention provides compounds of formula IId1

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IId1において:
ZおよびY₁は、上記式IIについて定義されたとおりであり;
任意のアルキレン基またはアルケニレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₁は、１回以上存在する場合、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、アミノアルキル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから独立して選択され、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、アミノアルキル、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;そして
R₂およびR₇は、式IIdについて定義されたとおりである。

And a pharmaceutically acceptable salt and solvate thereof, in Formula IId1:
Z and Y ₁ are as defined for Formula II above;
Any alkylene or alkenylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino; and
R ₂ and R ₇ are as defined for formula IId.

  The present invention further provides Formula III

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIIにおいて:
Y、Y₁、Y₂、およびY₃は、式IIについて定義されたとおりであり;
Y₄は、必要に応じて存在し、そして存在する場合、アリール、ヘテロアリール、炭素環、または複素環であり、ここで任意の環原子は独立して、ハロ、C_1〜5アルキル、ニトロ、シアノ、トリハロメチル、C_1〜5アルコキシ、C-アミド、N-アミド、スルホンアミド、アミノ、アミノスルホニル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、スルフィニルで必要に応じて置換されており、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;
o、p、およびqは各々独立して、0、1、または2であり;
o領域、p領域、およびq領域、ならびにY₂の任意のアルキレン基またはアルケニレン基は、非置換C_1〜4アルキル、ハロ、非置換C_1〜4ハロアルキル、または非置換C₃もしくはC₄シクロアルキルで必要に応じて置換されており;
ただし、pが0であり、Y₁が二価のフェニルであり、Y₂が-C(=O)N(H)-または-OC(H)₂C(=O)N(H)-であり、そしてY₃がフェニルまたはピリジニルである場合、Y₄が存在するか、またはY₃上の置換基はいずれも-C(=O)NH₂ではないかのいずれかであり;そして
ただし、この化合物は:
1-(6-メトキシ-3-ピリジル)-3-[[4-(3-ピリジルメトキシ)フェニル]メチル]尿素;
1-[(6-メトキシピリジン-3-イル)メチル]-3-[3-(3-メチルフェノキシ)プロピル]尿素;
1-[3-(2-フルオロフェノキシ)プロピル]-3-[(6-メトキシピリジン-3-イル)メチル]尿素;
3-(ピリジン-3-イル)-4-({4-[(3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}ベンジル)オキシ]フェニル}スルホニル)ブタン酸エチル;
4-({4-[(3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}ベンジル)オキシ]フェニル}スルホニル)-3-[4-(トリフルオロメチル)フェニル]ブタン酸;
3-フェニル-4-({4-[(3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}ベンジル)オキシ]フェニル}スルホニル)ブタン酸;
3-(4-クロロ-3-フルオロフェニル)-4-[(4-{[3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}-5-(トリフルオロメチル)ベンジル]オキシ}フェニル)スルホニル]ブタン酸;
3-フェニル-4-[(4-{[3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}-5-(トリフルオロメチル)ベンジル]オキシ}フェニル)スルホニル]ブタン酸;
3-(ピリジン-3-イル)-4-({4-[(3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}ベンジル)オキシ]フェニル}スルホニル)ブタン酸;
4-({4-[(4-フルオロ-3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}ベンジル)オキシ]フェニル}スルホニル)-3-(ピリジン-3-イル)ブタン酸;
安息香酸,2-ヒドロキシ-4-[[(3-ピリジニルアミノ)カルボニル]アミノ]-,フェニルエステル;
ベンズアミド,N-(3-アミノ-4-ピリジニル)-4-[[[[(3-ピリジニルメチル)アミノ]カルボニル]アミノ]メチル]-;
ベンズアミド,N-(2-アミノ-3-ピリジニル)-4-[[[[(3-ピリジニルメチル)アミノ]カルボニル]アミノ]メチル]-;
ベンズアミド,N-(2-アミノ-5-フルオロフェニル)-4-[[[[(3-ピリジニルメチル)アミノ]カルボニル]アミノ]メチル]-;
ベンズアミド,N-(2-ヒドロキシフェニル)-4-[[[[(3-ピリジニルメチル)アミノ]カルボニル]アミノ]メチル]-;
ベンズアミド,N-(2-アミノ-5-クロロフェニル)-4-[[[[(3-ピリジニルメチル)アミノ]カルボニル]アミノ]メチル]-;
ベンズアミド,2-クロロ-5-ニトロ-N-[4-[[(4-ピリジニルアミノ)カルボニル]アミノ]フェニル]-;
ベンズアミド,N-[4-[[[3-(ジエチルアミノ)プロピル]アミノ]カルボニル]フェニル]-4-[[(3-ピリジニルアミノ)カルボニル]アミノ]-;
ベンズアミド,N-(2-アミノフェニル)-4-[[[(3-ピリジニルアミノ)カルボニル]アミノ]メチル]-;
ベンズアミド,N-(2-アミノフェニル)-4-[2-[[[(3-ピリジニルメチル)アミノ]カルボニル]アミノ]エチル]-;
ベンズアミド,N-(2-アミノフェニル)-4-[[[[(3-ピリジニルメチル)アミノ]カルボニル]アミノ]メチル]-;
安息香酸,2-ヒドロキシ-4-[[(3-ピリジニルアミノ)カルボニル]アミノ]-,フェニルエステル;
1,3-ベンゼンジカルボキサミド,N,N'-ビス[3-(ジエチルアミノ)プロピル]-5-[[4-[[(4-ピリジニルアミノ)カルボニル]アミノ]ベンゾイル]アミノ]-;
尿素,N-[4-(フェニルメトキシ)フェニル]-N'-[2-(3-ピリジニル)エチル]-;
尿素,N-[4-(フェニルメトキシ)フェニル]-N'-3-ピリジニル-;
尿素,N-(6-メチル-3-ピリジニル)-N'-[2-[2-(フェニルメトキシ)フェニル]エチル]-;
尿素,N-(6-メトキシ-3-ピリジニル)-N'-[4-(フェニルメトキシ)フェニル]-;
4,6-ピリミジンジカルボキサミド,N4-[[4-[[[(2,6-ジクロロ-4-ピリジニル)アミノ]カルボニル]アミノ]フェニル]メチル]-N6-[(3-メトキシフェニル)メチル]-;
ベンゼンスルホンアミド,4-フルオロ-N-[4-[[(3-ピリジニルアミノ)カルボニル]アミノ]フェニル]-;または
ヘキサンアミド,2-[2,4-ビス(1,1-ジメチルプロピル)フェノキシ]-N-[2-クロロ-4-[[[(2-クロロ-3-ピリジニル)アミノ]カルボニル]アミノ]-5-ヒドロキシフェニル]-
ではない。

And the pharmaceutically acceptable salts and solvates thereof, in Formula III:
Y, Y ₁ , Y ₂ , and Y ₃ are as defined for Formula II;
Y ₄ is optionally present and, when present, is an aryl, heteroaryl, carbocycle, or heterocycle, wherein any ring atom is independently halo, C _1-5 alkyl, nitro , Cyano, trihalomethyl, C _1-5 alkoxy, C-amide, N-amide, sulfonamido, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, sulfinyl, optionally substituted, where C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
o, p, and q are each independently 0, 1, or 2;
o region, p region, and q region, and any alkylene or alkenylene group Y ₂ is unsubstituted C _{1 to 4} alkyl, halo, unsubstituted C _{1 to 4} haloalkyl or unsubstituted C ₃ or C ₄ cycloalkyl, Optionally substituted with alkyl;
However, p is 0, Y ₁ is divalent phenyl, Y ₂ is -C (= O) N (H)-or -OC (H) ₂ C (= O) N (H)- And when Y ₃ is phenyl or pyridinyl, either Y ₄ is present or any substituent on Y ₃ is not —C (═O) NH ₂ ; and This compound:
1- (6-methoxy-3-pyridyl) -3-[[4- (3-pyridylmethoxy) phenyl] methyl] urea;
1-[(6-methoxypyridin-3-yl) methyl] -3- [3- (3-methylphenoxy) propyl] urea;
1- [3- (2-fluorophenoxy) propyl] -3-[(6-methoxypyridin-3-yl) methyl] urea;
3- (pyridin-3-yl) -4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) butanoic acid ethyl;
4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) -3- [4- (trifluoromethyl) phenyl] butanoic acid;
3-phenyl-4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) butanoic acid;
3- (4-Chloro-3-fluorophenyl) -4-[(4-{[3-{[(pyridin-3-ylmethyl) carbamoyl] amino} -5- (trifluoromethyl) benzyl] oxy} phenyl) Sulfonyl] butanoic acid;
3-phenyl-4-[(4-{[3-{[(pyridin-3-ylmethyl) carbamoyl] amino} -5- (trifluoromethyl) benzyl] oxy} phenyl) sulfonyl] butanoic acid;
3- (pyridin-3-yl) -4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) butanoic acid;
4-({4-[(4-Fluoro-3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) -3- (pyridin-3-yl) butanoic acid;
Benzoic acid, 2-hydroxy-4-[[((3-pyridinylamino) carbonyl] amino]-, phenyl ester;
Benzamide, N- (3-amino-4-pyridinyl) -4-[[[[[(3-pyridinylmethyl) amino] carbonyl] amino] methyl]-;
Benzamide, N- (2-amino-3-pyridinyl) -4-[[[[[(3-pyridinylmethyl) amino] carbonyl] amino] methyl]-;
Benzamide, N- (2-amino-5-fluorophenyl) -4-[[[[[(3-pyridinylmethyl) amino] carbonyl] amino] methyl]-;
Benzamide, N- (2-hydroxyphenyl) -4-[[[[[(3-pyridinylmethyl) amino] carbonyl] amino] methyl]-;
Benzamide, N- (2-amino-5-chlorophenyl) -4-[[[[[(3-pyridinylmethyl) amino] carbonyl] amino] methyl]-;
Benzamide, 2-chloro-5-nitro-N- [4-[[(4-pyridinylamino) carbonyl] amino] phenyl]-;
Benzamide, N- [4-[[[3- (diethylamino) propyl] amino] carbonyl] phenyl] -4-[[(3-pyridinylamino) carbonyl] amino]-;
Benzamide, N- (2-aminophenyl) -4-[[[[(3-pyridinylamino) carbonyl] amino] methyl]-;
Benzamide, N- (2-aminophenyl) -4- [2-[[[[(3-pyridinylmethyl) amino] carbonyl] amino] ethyl]-;
Benzamide, N- (2-aminophenyl) -4-[[[[[(3-pyridinylmethyl) amino] carbonyl] amino] methyl]-;
Benzoic acid, 2-hydroxy-4-[[((3-pyridinylamino) carbonyl] amino]-, phenyl ester;
1,3-benzenedicarboxamide, N, N'-bis [3- (diethylamino) propyl] -5-[[4-[[(4-pyridinylamino) carbonyl] amino] benzoyl] amino]-;
Urea, N- [4- (phenylmethoxy) phenyl] -N '-[2- (3-pyridinyl) ethyl]-;
Urea, N- [4- (phenylmethoxy) phenyl] -N'-3-pyridinyl-;
Urea, N- (6-methyl-3-pyridinyl) -N '-[2- [2- (phenylmethoxy) phenyl] ethyl]-;
Urea, N- (6-methoxy-3-pyridinyl) -N '-[4- (phenylmethoxy) phenyl]-;
4,6-pyrimidinedicarboxamide, N4-[[4-[[[(2,6-dichloro-4-pyridinyl) amino] carbonyl] amino] phenyl] methyl] -N6-[(3-methoxyphenyl) methyl] -;
Benzenesulfonamide, 4-fluoro-N- [4-[[(3-pyridinylamino) carbonyl] amino] phenyl]-; or hexaneamide, 2- [2,4-bis (1,1-dimethylpropyl) phenoxy] -N- [2-chloro-4-[[[(2-chloro-3-pyridinyl) amino] carbonyl] amino] -5-hydroxyphenyl]-
is not.

  In some embodiments, the present invention provides compounds of formula IIIa

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIIaにおいて:
Yは、3-ピリジニルまたは4-ピリジニルであり、必要に応じて、式IについてのYについて定義されたように置換されており;
Y₂、Y₃、Y₄、およびqは、上記式IIIについて定義されたとおりであり;
nは、3、4、5、6、または7であり;そして
Y₂ならびにn領域およびq領域の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されている。

And a pharmaceutically acceptable salt and solvate thereof, in Formula IIIa:
Y is 3-pyridinyl or 4-pyridinyl, optionally substituted as defined for Y for formula I;
Y ₂ , Y ₃ , Y ₄ , and q are as defined for Formula III above;
n is 3, 4, 5, 6, or 7; and
Y ₂ and any methylene group in the n and q regions are independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl.

  In some embodiments, the present invention provides compounds of formula IIIa1

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIIa1において:
Yは、3-ピリジニルまたは4-ピリジニルであり、必要に応じて、式IについてのYについて定義されたように置換されており;
Y₃、Y₄、およびqは、上記式IIIについて定義されたとおりであり;
nは、3、4、5、6、または7であり;
n領域およびq領域の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;そして
R₃およびR₄は各々独立して、H、ハロ、またはC_1〜4アルキルであるか、あるいはR₃およびR₄は一緒になって、シクロプロピル環またはシクロブチル環を形成する。

And the pharmaceutically acceptable salts and solvates thereof, in Formula IIIa1:
Y is 3-pyridinyl or 4-pyridinyl, optionally substituted as defined for Y for formula I;
Y ₃ , Y ₄ , and q are as defined for Formula III above;
n is 3, 4, 5, 6, or 7;
any methylene group in the n and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl; and
R ₃ and R ₄ are each independently H, halo, or C _1-4 alkyl, or R ₃ and R ₄ together form a cyclopropyl or cyclobutyl ring.

  In some embodiments, the present invention provides compounds of formula IIIa2

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIIa2において:
Yは、3-ピリジニルまたは4-ピリジニルであり、必要に応じて、式IについてのYについて定義されたように置換されており;
Y₃、Y₄、およびqは、上記式IIIについて定義されたとおりであり;
nは、3、4、5、6、または7であり;
n領域およびq領域の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;そして
R₂は、H、ハロ、C_1〜5アルキル、C_1〜5アルケニル、またはC_1〜5アルキニルである。

And a pharmaceutically acceptable salt and solvate thereof, in Formula IIIa2:
Y is 3-pyridinyl or 4-pyridinyl, optionally substituted as defined for Y for formula I;
Y ₃ , Y ₄ , and q are as defined for Formula III above;
n is 3, 4, 5, 6, or 7;
any methylene group in the n and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl; and
R ₂ is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl.

  In some embodiments, the present invention provides compounds of formula IIIa3

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIIa3において:
Yは、3-ピリジニルまたは4-ピリジニルであり、必要に応じて、式IについてのYについて定義されたように置換されており;
Y₄およびqは、上記式IIIについて定義されたとおりであり;
nは、3、4、5、6、または7であり;
n領域およびq領域の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₁は、１回以上存在する場合、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、アミノアルキル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから独立して選択され、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、アミノアルキル、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;そして
R₃およびR₄は各々独立して、H、ハロ、またはC_1〜4アルキルであるか、あるいはR₃およびR₄は、これらが結合している炭素と一緒になって、シクロプロピル環またはシクロブチル環を形成する。

And the pharmaceutically acceptable salts and solvates thereof, in Formula IIIa3:
Y is 3-pyridinyl or 4-pyridinyl, optionally substituted as defined for Y for formula I;
Y ₄ and q are as defined for Formula III above;
n is 3, 4, 5, 6, or 7;
any methylene group in the n and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino; and
R ₃ and R ₄ are each independently H, halo, or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which they are attached, a cyclopropyl ring or A cyclobutyl ring is formed.

  In some embodiments, the present invention provides compounds of formula IIIa4

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIIa4において:
Yは、3-ピリジニルまたは4-ピリジニルであり、必要に応じて、式IについてのYについて定義されたように置換されており;
Y₄およびqは、上記式IIIについて定義されたとおりであり;
nは、3、4、5、6、または7であり;
n領域およびq領域の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₁は、１回以上存在する場合、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、アミノアルキル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから独立して選択され、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、アミノアルキル、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;そして
R₂は、H、ハロ、C_1〜5アルキル、C_1〜5アルケニル、またはC_1〜5アルキニルである。

And the pharmaceutically acceptable salts and solvates thereof, in Formula IIIa4:
Y is 3-pyridinyl or 4-pyridinyl, optionally substituted as defined for Y for formula I;
Y ₄ and q are as defined for Formula III above;
n is 3, 4, 5, 6, or 7;
any methylene group in the n and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino; and
R ₂ is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl.

  In some embodiments, the present invention provides compounds of formula IIIa5

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIIa5において:
Yは、3-ピリジニルまたは4-ピリジニルであり、必要に応じて、式IについてのYについて定義されたように置換されており;
qは、上記式IIIについて定義されたとおりであり;
nは、3、4、5、6、または7であり;
n領域およびq領域の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₁およびR₅は、一方または両方が１回以上存在する場合、各々独立して、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、アミノアルキル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから選択され、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、アミノアルキル、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;そして
R₃およびR₄は各々独立して、H、ハロ、またはC_1〜4アルキルであるか、あるいはR₃およびR₄は、これらが結合している炭素と一緒になって、シクロプロピル環またはシクロブチル環を形成する。

And the pharmaceutically acceptable salts and solvates thereof, in Formula IIIa5:
Y is 3-pyridinyl or 4-pyridinyl, optionally substituted as defined for Y for formula I;
q is as defined for Formula III above;
n is 3, 4, 5, 6, or 7;
any methylene group in the n and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₁ and R ₅ , when one or both are present more than once, are each independently halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalo Selected from methyl, C-carboxy, O-carboxy, sulfonamido, amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amido, amino, aminoalkyl, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino; and
R ₃ and R ₄ are each independently H, halo, or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which they are attached, a cyclopropyl ring or A cyclobutyl ring is formed.

  In some embodiments, the present invention provides compounds of formula IIIa6

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIIa6において:
Yは、3-ピリジニルまたは4-ピリジニルであり、必要に応じて、式IについてのYについて定義されたように置換されており;
qは、上記式IIIについて定義されたとおりであり;
nは、3、4、5、6、または7であり;
n領域およびq領域の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₁は、１回以上存在する場合、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、アミノアルキル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから独立して選択され、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、アミノアルキル、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;そして
R₂は、H、ハロ、C_1〜5アルキル、C_1〜5アルケニル、またはC_1〜5アルキニルである。

And a pharmaceutically acceptable salt and solvate thereof, in Formula IIIa6:
Y is 3-pyridinyl or 4-pyridinyl, optionally substituted as defined for Y for formula I;
q is as defined for Formula III above;
n is 3, 4, 5, 6, or 7;
any methylene group in the n and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino; and
R ₂ is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl.

  In some embodiments, the present invention provides compounds of formula IIIb

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIIbにおいて:
Yは、3-ピリジニルまたは4-ピリジニルであり、必要に応じて、式IについてのYについて定義されたように置換されており;
o、p、q、Y₂、Y₃、およびY₄は、上記式IIIについて定義されたとおりであり;
o領域、p領域、およびq領域、ならびにY₂の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₆は、１回以上存在する場合、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから独立して選択され;
ここでS、T、U、およびVは、炭素または窒素であり、ただし、S、T、U、またはVが窒素である場合、この窒素上に置換基は存在せず;
ただし、pが0であり、Y₂が-C(=O)N(H)-または-OC(H)₂C(=O)N(H)-であり、そしてY₃がフェニルまたはピリジニルである場合、Y₄は存在しないか、またはY₃上のいずれの置換基も-C(=O)NH₂ではないかのいずれかであり;そして
ただし、この化合物は、
1-(6-メトキシ-3-ピリジル)-3-[[4-(3-ピリジルメトキシ)フェニル]メチル]尿素、
3-(ピリジン-3-イル)-4-({4-[(3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}ベンジル)オキシ]フェニル}スルホニル)ブタン酸エチル;
4-({4-[(3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}ベンジル)オキシ]フェニル}スルホニル)-3-[4-(トリフルオロメチル)フェニル]ブタン酸;
3-フェニル-4-({4-[(3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}ベンジル)オキシ]フェニル}スルホニル)ブタン酸;
3-(4-クロロ-3-フルオロフェニル)-4-[(4-{[3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}-5-(トリフルオロメチル)ベンジル]オキシ}フェニル)スルホニル]ブタン酸;
3-フェニル-4-[(4-{[3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}-5-(トリフルオロメチル)ベンジル]オキシ}フェニル)スルホニル]ブタン酸;
3-(ピリジン-3-イル)-4-({4-[(3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}ベンジル)オキシ]フェニル}スルホニル)ブタン酸;
4-({4-[(4-フルオロ-3-{[(ピリジン-3-イルメチル)カルバモイル]アミノ}ベンジル)オキシ]フェニル}スルホニル)-3-(ピリジン-3-イル)ブタン酸;
安息香酸,2-ヒドロキシ-4-[[(3-ピリジニルアミノ)カルボニル]アミノ]-,フェニルエステル、
ベンズアミド,N-(3-アミノ-4-ピリジニル)-4-[[[[(3-ピリジニルメチル)アミノ]カルボニル]アミノ]メチル]-、
ベンズアミド,N-(2-アミノ-3-ピリジニル)-4-[[[[(3-ピリジニルメチル)アミノ]カルボニル]アミノ]メチル]-、
ベンズアミド,N-(2-アミノ-5-フルオロフェニル)-4-[[[[(3-ピリジニルメチル)アミノ]カルボニル]アミノ]メチル]-、
ベンズアミド,N-(2-ヒドロキシフェニル)-4-[[[[(3-ピリジニルメチル)アミノ]カルボニル]アミノ]メチル]-、
ベンズアミド,N-(2-アミノ-5-クロロフェニル)-4-[[[[(3-ピリジニルメチル)アミノ]カルボニル]アミノ]メチル]-、
ベンズアミド,2-クロロ-5-ニトロ-N-[4-[[(4-ピリジニルアミノ)カルボニル]アミノ]フェニル]-、
ベンズアミド,N-[4-[[[3-(ジエチルアミノ)プロピル]アミノ]カルボニル]フェニル]-4-[[(3-ピリジニルアミノ)カルボニル]アミノ]-、
ベンズアミド,N-(2-アミノフェニル)-4-[[[(3-ピリジニルアミノ)カルボニル]アミノ]メチル]-、
ベンズアミド,N-(2-アミノフェニル)-4-[2-[[[(3-ピリジニルメチル)アミノ]カルボニル]アミノ]エチル]-、
ベンズアミド,N-(2-アミノフェニル)-4-[[[[(3-ピリジニルメチル)アミノ]カルボニル]アミノ]メチル]-、
安息香酸,2-ヒドロキシ-4-[[(3-ピリジニルアミノ)カルボニル]アミノ]-,フェニルエステル、
1,3-ベンゼンジカルボキサミド,N,N'-ビス[3-(ジエチルアミノ)プロピル]-5-[[4-[[(4-ピリジニルアミノ)カルボニル]アミノ]ベンゾイル]アミノ]-、
尿素,N-[4-(フェニルメトキシ)フェニル]-N'-[2-(3-ピリジニル)エチル]-、
尿素,N-[4-(フェニルメトキシ)フェニル]-N'-3-ピリジニル-、
尿素,N-(6-メチル-3-ピリジニル)-N'-[2-[2-(フェニルメトキシ)フェニル]エチル]-、
尿素,N-(6-メトキシ-3-ピリジニル)-N'-[4-(フェニルメトキシ)フェニル]-、
4,6-ピリミジンジカルボキサミド,N4-[[4-[[[(2,6-ジクロロ-4-ピリジニル)アミノ]カルボニル]アミノ]フェニル]メチル]-N6-[(3-メトキシフェニル)メチル]-、
ベンゼンスルホンアミド,4-フルオロ-N-[4-[[(3-ピリジニルアミノ)カルボニル]アミノ]フェニル]-、または
ヘキサンアミド,2-[2,4-ビス(1,1-ジメチルプロピル)フェノキシ]-N-[2-クロロ-4-[[[(2-クロロ-3-ピリジニル)アミノ]カルボニル]アミノ]-5-ヒドロキシフェニル]-
ではない。

And the pharmaceutically acceptable salts and solvates thereof, in Formula IIIb:
Y is 3-pyridinyl or 4-pyridinyl, optionally substituted as defined for Y for formula I;
o, p, q, Y ₂ , Y ₃ , and Y ₄ are as defined above for Formula III;
o region, p region, and q region, and any methylene group of Y ₂ is independently C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl as required Has been replaced;
R ₆ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide Independently selected from, amino, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl;
Where S, T, U, and V are carbon or nitrogen, provided that when S, T, U, or V is nitrogen, there are no substituents on the nitrogen;
Where p is 0, Y ₂ is —C (═O) N (H) — or —OC (H) ₂ C (═O) N (H) —, and Y ₃ is phenyl or pyridinyl In some cases, Y ₄ is either absent or any substituent on Y ₃ is not -C (= O) NH ₂ ; and
1- (6-methoxy-3-pyridyl) -3-[[4- (3-pyridylmethoxy) phenyl] methyl] urea,
3- (pyridin-3-yl) -4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) butanoic acid ethyl;
4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) -3- [4- (trifluoromethyl) phenyl] butanoic acid;
3-phenyl-4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) butanoic acid;
3- (4-Chloro-3-fluorophenyl) -4-[(4-{[3-{[(pyridin-3-ylmethyl) carbamoyl] amino} -5- (trifluoromethyl) benzyl] oxy} phenyl) Sulfonyl] butanoic acid;
3-phenyl-4-[(4-{[3-{[(pyridin-3-ylmethyl) carbamoyl] amino} -5- (trifluoromethyl) benzyl] oxy} phenyl) sulfonyl] butanoic acid;
3- (pyridin-3-yl) -4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) butanoic acid;
4-({4-[(4-Fluoro-3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) -3- (pyridin-3-yl) butanoic acid;
Benzoic acid, 2-hydroxy-4-[[(3-pyridinylamino) carbonyl] amino]-, phenyl ester,
Benzamide, N- (3-amino-4-pyridinyl) -4-[[[[[(3-pyridinylmethyl) amino] carbonyl] amino] methyl]-,
Benzamide, N- (2-amino-3-pyridinyl) -4-[[[[[(3-pyridinylmethyl) amino] carbonyl] amino] methyl]-,
Benzamide, N- (2-amino-5-fluorophenyl) -4-[[[[[(3-pyridinylmethyl) amino] carbonyl] amino] methyl]-,
Benzamide, N- (2-hydroxyphenyl) -4-[[[[[(3-pyridinylmethyl) amino] carbonyl] amino] methyl]-,
Benzamide, N- (2-amino-5-chlorophenyl) -4-[[[[[(3-pyridinylmethyl) amino] carbonyl] amino] methyl]-,
Benzamide, 2-chloro-5-nitro-N- [4-[[(4-pyridinylamino) carbonyl] amino] phenyl]-,
Benzamide, N- [4-[[[3- (diethylamino) propyl] amino] carbonyl] phenyl] -4-[[((3-pyridinylamino) carbonyl] amino]-,
Benzamide, N- (2-aminophenyl) -4-[[[[(3-pyridinylamino) carbonyl] amino] methyl]-,
Benzamide, N- (2-aminophenyl) -4- [2-[[[[(3-pyridinylmethyl) amino] carbonyl] amino] ethyl]-,
Benzamide, N- (2-aminophenyl) -4-[[[[[(3-pyridinylmethyl) amino] carbonyl] amino] methyl]-,
Benzoic acid, 2-hydroxy-4-[[(3-pyridinylamino) carbonyl] amino]-, phenyl ester,
1,3-benzenedicarboxamide, N, N′-bis [3- (diethylamino) propyl] -5-[[4-[[(4-pyridinylamino) carbonyl] amino] benzoyl] amino]-,
Urea, N- [4- (phenylmethoxy) phenyl] -N ′-[2- (3-pyridinyl) ethyl]-,
Urea, N- [4- (phenylmethoxy) phenyl] -N'-3-pyridinyl-,
Urea, N- (6-methyl-3-pyridinyl) -N '-[2- [2- (phenylmethoxy) phenyl] ethyl]-,
Urea, N- (6-methoxy-3-pyridinyl) -N ′-[4- (phenylmethoxy) phenyl]-,
4,6-pyrimidinedicarboxamide, N4-[[4-[[[(2,6-dichloro-4-pyridinyl) amino] carbonyl] amino] phenyl] methyl] -N6-[(3-methoxyphenyl) methyl] -,
Benzenesulfonamide, 4-fluoro-N- [4-[[(3-pyridinylamino) carbonyl] amino] phenyl]-, or hexaneamide, 2- [2,4-bis (1,1-dimethylpropyl) phenoxy] -N- [2-chloro-4-[[[(2-chloro-3-pyridinyl) amino] carbonyl] amino] -5-hydroxyphenyl]-
is not.

  In some embodiments, the present invention provides compounds of formula IIIb1

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIIb1において:
Yは、3-ピリジニルまたは4-ピリジニルであり、必要に応じて、式IについてのYについて定義されたように置換されており;
o、p、q、Y₃、およびY₄は、上記式IIIについて定義されたとおりであり;
o領域、p領域、およびq領域の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₃およびR₄は各々独立して、H、ハロ、またはC_1〜4アルキルであるか、あるいはR₃およびR₄は、これらが結合している炭素と一緒になって、シクロプロピル環またはシクロブチル環を形成し;そして
R₆は、上記式IIIbについて定義されたとおりである。

And the pharmaceutically acceptable salts and solvates thereof, in Formula IIIb1:
Y is 3-pyridinyl or 4-pyridinyl, optionally substituted as defined for Y for formula I;
o, p, q, Y ₃ , and Y ₄ are as defined for Formula III above;
Any methylene group in the o, p, and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. ;
R ₃ and R ₄ are each independently H, halo, or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which they are attached, a cyclopropyl ring or Forming a cyclobutyl ring; and
R ₆ is as defined for Formula IIIb above.

  In some embodiments, the present invention provides compounds of formula IIIb2

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIIb2において:
Yは、3-ピリジニルまたは4-ピリジニルであり、必要に応じて、式IについてのYについて定義されたように置換されており;
o、p、q、Y₃、およびY₄は、上記式IIIについて定義されたとおりであり;
o領域、p領域、およびq領域の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₆は、上記式IIIbについて定義されたとおりであり;そして
R₂は、H、ハロ、C_1〜5アルキル、C_1〜5アルケニル、またはC_1〜5アルキニルである。

And the pharmaceutically acceptable salts and solvates thereof, in Formula IIIb2:
Y is 3-pyridinyl or 4-pyridinyl, optionally substituted as defined for Y for formula I;
o, p, q, Y ₃ , and Y ₄ are as defined for Formula III above;
Any methylene group in the o, p, and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. ;
R ₆ is as defined above for Formula IIIb; and
R ₂ is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl.

  In some embodiments, the present invention provides compounds of formula IIIb3

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIIb3において:
Yは、3-ピリジニルまたは4-ピリジニルであり、必要に応じて、式IについてのYについて定義されたように置換されており;
o、p、q、Y₃、およびY₄は、上記式IIIについて定義されたとおりであり;
uは、0または1であり;
o領域、p領域、q領域、およびu領域の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;そして
R₆は、上記式IIIbについて定義されたとおりである。

And the pharmaceutically acceptable salts and solvates thereof, in Formula IIIb3:
Y is 3-pyridinyl or 4-pyridinyl, optionally substituted as defined for Y for formula I;
o, p, q, Y ₃ , and Y ₄ are as defined for Formula III above;
u is 0 or 1;
Any methylene group in the o, p, q, and u regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. Have been; and
R ₆ is as defined for Formula IIIb above.

  In some embodiments, the present invention provides compounds of formula IIIb4

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIIb4において:
Yは、3-ピリジニルまたは4-ピリジニルであり、必要に応じて、式IについてのYについて定義されたように置換されており;
o、p、q、およびY₄は、上記式IIIについて定義されたとおりであり;
R₁は、１回以上存在する場合、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、アミノアルキル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから独立して選択され、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、アミノアルキル、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;
R₃およびR₄は各々独立して、H、ハロ、またはC_1〜4アルキルであるか、あるいはR₃およびR₄は、これらが結合している炭素と一緒になって、シクロプロピル環またはシクロブチル環を形成し;
R₆は、上記式IIIbについて定義されたとおりであり;そして
o領域、p領域、およびq領域の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されている。

And the pharmaceutically acceptable salts and solvates thereof, in Formula IIIb4:
Y is 3-pyridinyl or 4-pyridinyl, optionally substituted as defined for Y for formula I;
o, p, q, and Y ₄ are as defined above for Formula III;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₃ and R ₄ are each independently H, halo, or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which they are attached, a cyclopropyl ring or Forming a cyclobutyl ring;
R ₆ is as defined above for Formula IIIb; and
Any methylene group in the o, p, and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. .

  In some embodiments, the present invention provides compounds of formula IIIb5

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIIb5において:
Yは、3-ピリジニルまたは4-ピリジニルであり、必要に応じて、式IについてのYについて定義されたように置換されており;
o、p、q、およびY₄は、上記式IIIについて定義されたとおりであり;
R₁は、１回以上存在する場合、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、アミノアルキル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから独立して選択され、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、アミノアルキル、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;
R₂は、H、ハロ、C_1〜5アルキル、C_1〜5アルケニル、またはC_1〜5アルキニルであり;
R₆は、上記式IIIbについて定義されたとおりであり;そして
o領域、p領域、およびq領域の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されている。

And the pharmaceutically acceptable salts and solvates thereof, in Formula IIIb5:
Y is 3-pyridinyl or 4-pyridinyl, optionally substituted as defined for Y for formula I;
o, p, q, and Y ₄ are as defined above for Formula III;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₂ is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl;
R ₆ is as defined above for Formula IIIb; and
Any methylene group in the o, p, and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. .

  In some embodiments, the present invention provides compounds of formula IIIb6

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIIb6において:
Yは、3-ピリジニルまたは4-ピリジニルであり、必要に応じて、式IについてのYについて定義されたように置換されており;
o、p、q、およびY₄は、上記式IIIについて定義されたとおりであり;
uは、0または1であり;
R₁は、１回以上存在する場合、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、アミノアルキル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから独立して選択され、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、アミノアルキル、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;
R₆は、上記式IIIbについて定義されたとおりであり;そして
o領域、p領域、q領域、およびu領域の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されている。

And the pharmaceutically acceptable salts and solvates thereof, in Formula IIIb6:
Y is 3-pyridinyl or 4-pyridinyl, optionally substituted as defined for Y for formula I;
o, p, q, and Y ₄ are as defined above for Formula III;
u is 0 or 1;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₆ is as defined above for Formula IIIb; and
Any methylene group in the o, p, q, and u regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. Has been.

  In some embodiments, the present invention provides compounds of formula IIIb7

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIIb7において:
Yは、3-ピリジニルまたは4-ピリジニルであり、必要に応じて、式IについてのYについて定義されたように置換されており;
o、p、およびqは、上記式IIIについて定義されたとおりであり;
R₁およびR₅は、一方または両方が１回以上存在する場合、各々独立して、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、アミノアルキル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから選択され、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、アミノアルキル、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;
R₃およびR₄は各々独立して、H、ハロ、またはC_1〜4アルキルであるか、あるいはR₃およびR₄は、これらが結合している炭素と一緒になって、シクロプロピル環またはシクロブチル環を形成し;
R₆は、上記式IIIbについて定義されたとおりであり;そして
o領域、p領域、およびq領域の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されている。

And the pharmaceutically acceptable salts and solvates thereof, in Formula IIIb7:
Y is 3-pyridinyl or 4-pyridinyl, optionally substituted as defined for Y for formula I;
o, p, and q are as defined above for Formula III;
R ₁ and R ₅ , when one or both are present more than once, are each independently halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalo Selected from methyl, C-carboxy, O-carboxy, sulfonamido, amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amido, amino, aminoalkyl, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₃ and R ₄ are each independently H, halo, or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which they are attached, a cyclopropyl ring or Forming a cyclobutyl ring;
R ₆ is as defined above for Formula IIIb; and
Any methylene group in the o, p, and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. .

  In some embodiments, the present invention provides compounds of formula IIIb8

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIIb8において:
Yは、3-ピリジニルまたは4-ピリジニルであり、必要に応じて、式IについてのYについて定義されたように置換されており;
o、p、およびqは、上記式IIIについて定義されたとおりであり;
R₁およびR₅は、一方または両方が１回以上存在する場合、各々独立して、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、アミノアルキル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから選択され、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、アミノアルキル、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;
R₂は、H、ハロ、C_1〜5アルキル、C_1〜5アルケニル、またはC_1〜5アルキニルであり;
R₆は、上記式IIIbについて定義されたとおりであり;そして
o領域、p領域、およびq領域の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されている。

And the pharmaceutically acceptable salts and solvates thereof, in Formula IIIb8:
Y is 3-pyridinyl or 4-pyridinyl, optionally substituted as defined for Y for formula I;
o, p, and q are as defined above for Formula III;
R ₁ and R ₅ , when one or both are present more than once, are each independently halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalo Selected from methyl, C-carboxy, O-carboxy, sulfonamido, amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amido, amino, aminoalkyl, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₂ is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl;
R ₆ is as defined above for Formula IIIb; and
Any methylene group in the o, p, and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. .

  In some embodiments, the present invention provides compounds of formula IIIb9

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIIb9において:
Yは、3-ピリジニルまたは4-ピリジニルであり、必要に応じて、式IについてのYについて定義されたように置換されており;
o、p、およびqは、式IIIについて定義されたとおりであり;
uは、0または1であり;
R₁およびR₅は、一方または両方が１回以上存在する場合、各々独立して、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、アミノアルキル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから選択され、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、アミノアルキル、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;
R₆は、上記式IIIbにおいて定義されたとおりであり;そして
o領域、p領域、q領域、およびu領域の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されている。

And a pharmaceutically acceptable salt and solvate thereof, in Formula IIIb9:
Y is 3-pyridinyl or 4-pyridinyl, optionally substituted as defined for Y for formula I;
o, p, and q are as defined for Formula III;
u is 0 or 1;
R ₁ and R ₅ , when one or both are present more than once, are each independently halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalo Selected from methyl, C-carboxy, O-carboxy, sulfonamido, amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amido, amino, aminoalkyl, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₆ is as defined above in formula IIIb; and
Any methylene group in the o, p, q, and u regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. Has been.

  In some embodiments, the present invention provides compounds of formula IIIb10

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIIb10において:
Yは、3-ピリジニルまたは4-ピリジニルであり、必要に応じて、式IについてのYについて定義されたように置換されており;
o、p、およびqは、上記式IIIについて定義されたとおりであり;
R₁およびR₅は、一方または両方が１回以上存在する場合、各々独立して、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、アミノアルキル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから選択され、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、アミノアルキル、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;
R₃およびR₄は各々独立して、H、ハロ、またはC_1〜4アルキルであるか、あるいはR3およびR4は、これらが結合している炭素と一緒になって、シクロプロピル環またはシクロブチル環を形成し;
R₆は、上記式IIIbについて定義されたとおりであり;
o領域、p領域、およびq領域の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;そして
S、T、U、およびVは、炭素または窒素であり、ただし、S、T、U、およびVのうちの少なくとも１つは窒素であり、そしてS、T、U、またはVが窒素である場合、この窒素上に置換基は存在しない。

And a pharmaceutically acceptable salt and solvate thereof, in Formula IIIb10:
Y is 3-pyridinyl or 4-pyridinyl, optionally substituted as defined for Y for formula I;
o, p, and q are as defined above for Formula III;
R ₁ and R ₅ , when one or both are present more than once, are each independently halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalo Selected from methyl, C-carboxy, O-carboxy, sulfonamido, amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amido, amino, aminoalkyl, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₃ and R ₄ are each independently H, halo, or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which they are attached, a cyclopropyl or cyclobutyl ring Forming;
R ₆ is as defined for Formula IIIb above;
Any methylene group in the o, p, and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. ; And
S, T, U, and V are carbon or nitrogen, provided that at least one of S, T, U, and V is nitrogen and S, T, U, or V is nitrogen If present, there are no substituents on this nitrogen.

  In some embodiments, the present invention provides compounds of formula IIIb11

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIIb11において:
Yは、3-ピリジニルまたは4-ピリジニルであり、必要に応じて、式IについてのYについて定義されたように置換されており;
o、p、およびqは、上記式IIIについて定義されたとおりであり;
R₁は、一方または両方が１回以上存在する場合、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、アミノアルキル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから独立して選択され、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、アミノアルキル、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;
R₂は、H、ハロ、C_1〜5アルキル、C_1〜5アルケニル、またはC_1〜5アルキニルであり;
R₆は、上記式IIIbについて定義されたとおりであり;
o領域、p領域、およびq領域の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;そして
S、T、U、およびVは、炭素または窒素であり、ただし、S、T、U、およびVのうちの少なくとも１つは窒素であり、そしてS、T、U、またはVが窒素である場合、この窒素上に置換基は存在しない。

And the pharmaceutically acceptable salts and solvates thereof, in Formula IIIb11:
Y is 3-pyridinyl or 4-pyridinyl, optionally substituted as defined for Y for formula I;
o, p, and q are as defined above for Formula III;
R ₁ is halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O— when one or both are present more than once Independently selected from carboxy, sulfonamide, amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino , Aminoalkyl, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₂ is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl;
R ₆ is as defined for Formula IIIb above;
Any methylene group in the o, p, and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. ; And
S, T, U, and V are carbon or nitrogen, provided that at least one of S, T, U, and V is nitrogen and S, T, U, or V is nitrogen If present, there are no substituents on this nitrogen.

  In some embodiments, the present invention provides compounds of formula IIIc

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IIIcにおいて:
Yは、3-ピリジニルまたは4-ピリジニルであり、必要に応じて、式IについてのYについて定義されたように置換されており;
Y₂、o、p、およびqは、式IIIについて定義されたとおりであり;
R₁およびR₅は、一方または両方が１回以上存在する場合、各々独立して、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、アミノアルキル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから選択され、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、アミノアルキル、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;
R₆は、１回以上存在する場合、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから独立して選択され;そして
o領域、p領域、およびq領域、またはY₂の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されている。

And the pharmaceutically acceptable salts and solvates thereof, in Formula IIIc:
Y is 3-pyridinyl or 4-pyridinyl, optionally substituted as defined for Y for formula I;
Y ₂ , o, p, and q are as defined for Formula III;
R ₁ and R ₅ , when one or both are present more than once, are each independently halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalo Selected from methyl, C-carboxy, O-carboxy, sulfonamido, amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amido, amino, aminoalkyl, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₆ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide Independently selected from, amino, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl; and
o-region, p-region, and q-region, or any methylene group in Y ₂ is independently C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl as required Has been replaced.

  The present invention further provides Formula IV

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IVにおいて:
o、p、q、Y、Y₁、Y₂、Y₃、およびY₄は、上記式IIIについて定義されたとおりであり;
ただし、Y₁が二価のフェニルであり、qが0であり、そしてpが1である場合、Y₄は存在し;
ただし、Y₁がC_2〜8アルキレンであり、そしてqが0である場合、Y₄は存在し;そして
ただし、この化合物は:
2-シアノ-1-[[4-[(4-フェニルフェニル)スルホニルアミノ]フェニル]メチル]-3-(4-ピリジル)グアニジン
ではない。

And the pharmaceutically acceptable salts and solvates thereof, in Formula IV:
o, p, q, Y, Y ₁ , Y ₂ , Y ₃ , and Y ₄ are as defined for Formula III above;
Provided that when Y ₁ is divalent phenyl, q is 0, and p is 1, Y ₄ is present;
Provided that when Y ₁ is C _2-8 alkylene and q is 0, Y ₄ is present; and
It is not 2-cyano-1-[[4-[(4-phenylphenyl) sulfonylamino] phenyl] methyl] -3- (4-pyridyl) guanidine.

  In some embodiments, the present invention provides compounds of formula IVa

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IVaにおいて:
Yは、3-ピリジニルまたは4-ピリジニルであり、必要に応じて、式IについてのYについて定義されたように置換されており;
Y₂、Y₃、Y₄、およびqは、上記式IVについて定義されたとおりであり;
nは、3、4、5、6、または7であり;そして
Y₂ならびにn領域およびq領域の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されている。

And the pharmaceutically acceptable salts and solvates thereof, in Formula IVa:
Y is 3-pyridinyl or 4-pyridinyl, optionally substituted as defined for Y for formula I;
Y ₂ , Y ₃ , Y ₄ , and q are as defined above for Formula IV;
n is 3, 4, 5, 6, or 7; and
Y ₂ and any methylene group in the n and q regions are independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl.

  In some embodiments, the present invention provides compounds of formula IVa1

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IVa1において:
Yは、上記式IVaについて定義されたとおりであり;
Y₃、Y₄、およびqは、上記式IVについて定義されたとおりであり;
nは、3、4、5、6、または7であり;
n領域およびq領域の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;そして
R₃およびR₄は各々独立して、H、ハロ、またはC_1〜4アルキルであるか、あるいはR₃およびR₄は一緒になって、シクロプロピル環またはシクロブチル環を形成する。

And a pharmaceutically acceptable salt and solvate thereof, in Formula IVa1:
Y is as defined for formula IVa above;
Y ₃ , Y ₄ , and q are as defined for Formula IV above;
n is 3, 4, 5, 6, or 7;
any methylene group in the n and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl; and
R ₃ and R ₄ are each independently H, halo, or C _1-4 alkyl, or R ₃ and R ₄ together form a cyclopropyl or cyclobutyl ring.

  In some embodiments, the present invention provides compounds of formula IVa2

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IVa2において:
Yは、上記式IVaについて定義されたとおりであり;
Y₃、Y₄、およびqは、上記式IVについて定義されたとおりであり;
nは、3、4、5、6、または7であり;
n領域およびq領域の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;そして
R₂は、H、ハロ、C_1〜5アルキル、C_1〜5アルケニル、またはC_1〜5アルキニルである。

And a pharmaceutically acceptable salt and solvate thereof, in Formula IVa2:
Y is as defined for formula IVa above;
Y ₃ , Y ₄ , and q are as defined for Formula IV above;
n is 3, 4, 5, 6, or 7;
any methylene group in the n and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl; and
R ₂ is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl.

  In some embodiments, the present invention provides compounds of formula IVa3

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IVa3において:
Yは、上記式IVaについて定義されたとおりであり;
Y₄およびqは、上記式IVについて定義されたとおりであり;
nは、3、4、5、6、または7であり;
n領域およびq領域の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₁は、１回以上存在する場合、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、アミノアルキル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから独立して選択され、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、アミノアルキル、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;そして
R₃およびR₄は各々独立して、H、ハロ、またはC_1〜4アルキルであるか、あるいはR₃およびR₄は、これらが結合している炭素と一緒になって、シクロプロピル環またはシクロブチル環を形成する。

And a pharmaceutically acceptable salt and solvate thereof, in Formula IVa3:
Y is as defined for formula IVa above;
Y ₄ and q are as defined for Formula IV above;
n is 3, 4, 5, 6, or 7;
any methylene group in the n and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino; and
R ₃ and R ₄ are each independently H, halo, or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which they are attached, a cyclopropyl ring or A cyclobutyl ring is formed.

  In some embodiments, the present invention provides compounds of formula IVa4

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IVa4において:
Yは、上記式IVaについて定義されたとおりであり;
Y₄およびqは、上記式IVについて定義されたとおりであり;
nは、3、4、5、6、または7であり;
n領域およびq領域の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₁は、１回以上存在する場合、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、アミノアルキル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから独立して選択され、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、アミノアルキル、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;そして
R₂は、H、ハロ、C_1〜5アルキル、C_1〜5アルケニル、またはC_1〜5アルキニルである。

And the pharmaceutically acceptable salts and solvates thereof, in Formula IVa4:
Y is as defined for formula IVa above;
Y ₄ and q are as defined for Formula IV above;
n is 3, 4, 5, 6, or 7;
any methylene group in the n and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino; and
R ₂ is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl.

  In some embodiments, the present invention provides compounds of formula IVa5

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IVa5において:
Yは、上記式IVaについて定義されたとおりであり;
qは、上記式IVについて定義されたとおりであり;
nは、3、4、5、6、または7であり;
n領域およびq領域の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₁およびR₅は、一方または両方が１回以上存在する場合、各々独立して、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、アミノアルキル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから選択され、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、アミノアルキル、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;そして
R₃およびR₄は各々独立して、H、ハロ、またはC_1〜4アルキルであるか、あるいはR₃およびR₄は、これらが結合している炭素と一緒になって、シクロプロピル環またはシクロブチル環を形成する。

And the pharmaceutically acceptable salts and solvates thereof, in Formula IVa5:
Y is as defined for formula IVa above;
q is as defined for Formula IV above;
n is 3, 4, 5, 6, or 7;
any methylene group in the n and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₁ and R ₅ , when one or both are present more than once, are each independently halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalo Selected from methyl, C-carboxy, O-carboxy, sulfonamido, amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amido, amino, aminoalkyl, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino; and
R ₃ and R ₄ are each independently H, halo, or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which they are attached, a cyclopropyl ring or A cyclobutyl ring is formed.

  In some embodiments, the present invention provides compounds of formula IVa6

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IVa6において:
Yは、上記式IVaについて定義されたとおりであり;
qは、上記式IVについて定義されたとおりであり;
nは、3、4、5、6、または7であり;
n領域およびq領域の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₁は、１回以上存在する場合、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、アミノアルキル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから独立して選択され、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、アミノアルキル、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;そして
R₂は、H、ハロ、C_1〜5アルキル、C_1〜5アルケニル、またはC_1〜5アルキニルである。

And the pharmaceutically acceptable salts and solvates thereof, in Formula IVa6:
Y is as defined for formula IVa above;
q is as defined for Formula IV above;
n is 3, 4, 5, 6, or 7;
any methylene group in the n and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino; and
R ₂ is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl.

  In some embodiments, the present invention provides compounds of formula IVb

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IVbにおいて:
Yは、3-ピリジニルまたは4-ピリジニルであり、必要に応じて、式IについてのYについて定義されたように置換されており;
o、p、q、Y₂、Y₃、およびY₄は、上記式IVについて定義されたとおりであり;
o領域、p領域、およびq領域、ならびにY₂の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₆は、１回以上存在する場合、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから独立して選択され;
ここでS、T、U、およびVは、炭素または窒素であり、ただし、S、T、U、またはVが窒素である場合、この窒素上に置換基は存在せず;
ただし、qが0であり、S、T、U、およびVが炭素であり、そしてpが1である場合、Y₄は存在し;そして
ただし、この化合物は、2-シアノ-1-[[4-[(4-フェニルフェニル)スルホニルアミノ]フェニル]メチル]-3-(4-ピリジル)グアニジンではない。

And the pharmaceutically acceptable salts and solvates thereof, in Formula IVb:
Y is 3-pyridinyl or 4-pyridinyl, optionally substituted as defined for Y for formula I;
o, p, q, Y ₂ , Y ₃ , and Y ₄ are as defined for Formula IV above;
o region, p region, and q region, and any methylene group of Y ₂ is independently C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl as required Has been replaced;
R ₆ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide Independently selected from, amino, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl;
Where S, T, U, and V are carbon or nitrogen, provided that when S, T, U, or V is nitrogen, there are no substituents on the nitrogen;
Provided that when q is 0, S, T, U, and V are carbon and p is 1, Y ₄ is present; and provided that the compound is 2-cyano-1-[[ It is not 4-[(4-phenylphenyl) sulfonylamino] phenyl] methyl] -3- (4-pyridyl) guanidine.

  In some embodiments, the present invention provides compounds of formula IVb1

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IVb1において:
YおよびR₆は、上記式IVbについて定義されたとおりであり;
o、p、q、Y₃、およびY₄は、上記式IVについて定義されたとおりであり;
o領域、p領域、およびq領域の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;そして
R₃およびR₄は各々独立して、H、ハロ、またはC_1〜4アルキルであるか、あるいはR₃およびR₄は、これらが結合している炭素と一緒になって、シクロプロピル環またはシクロブチル環を形成する。

And the pharmaceutically acceptable salts and solvates thereof, in Formula IVb1:
Y and R ₆ are as defined for formula IVb above;
o, p, q, Y ₃ , and Y ₄ are as defined above for Formula IV;
Any methylene group in the o, p, and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. ; And
R ₃ and R ₄ are each independently H, halo, or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which they are attached, a cyclopropyl ring or A cyclobutyl ring is formed.

  In some embodiments, the present invention provides compounds of formula IVb2

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IVb2において:
YおよびR₆は、上記式IVbについて定義されたとおりであり;
o、p、q、Y₃、およびY₄は、上記式IVについて定義されたとおりであり;
o領域、p領域、およびq領域の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;
R₂は、H、ハロ、C_1〜5アルキル、C_1〜5アルケニル、またはC_1〜5アルキニルであり;そして
ただし、この化合物は、2-シアノ-1-[[4-[(4-フェニルフェニル)スルホニルアミノ]フェニル]メチル]-3-(4-ピリジル)グアニジンではない。

And a pharmaceutically acceptable salt and solvate thereof, in Formula IVb2:
Y and R ₆ are as defined for formula IVb above;
o, p, q, Y ₃ , and Y ₄ are as defined above for Formula IV;
Any methylene group in the o, p, and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. ;
R ₂ is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl; and provided that the compound is 2-cyano-1-[[4-[(4- Not phenylphenyl) sulfonylamino] phenyl] methyl] -3- (4-pyridyl) guanidine.

  In some embodiments, the present invention provides compounds of formula IVb3

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IVb3において:
YおよびR₆は、上記式IVbについて定義されたとおりであり;
o、p、q、およびY₄は、上記式IVについて定義されたとおりであり;
R₁は、１回以上存在する場合、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、アミノアルキル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから独立して選択され、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、アミノアルキル、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;
R₃およびR₄は各々独立して、H、ハロ、またはC_1〜4アルキルであるか、あるいはR₃およびR₄は、これらが結合している炭素と一緒になって、シクロプロピル環またはシクロブチル環を形成し;そして
o領域、p領域、およびq領域の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されている。

And the pharmaceutically acceptable salts and solvates thereof, in Formula IVb3:
Y and R ₆ are as defined for formula IVb above;
o, p, q, and Y ₄ are as defined for Formula IV above;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₃ and R ₄ are each independently H, halo, or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which they are attached, a cyclopropyl ring or Forming a cyclobutyl ring; and
Any methylene group in the o, p, and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. .

  In some embodiments, the present invention provides compounds of formula IVb4

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IVb4において:
YおよびR₆は、上記式IVbについて定義されたとおりであり;
o、p、q、およびY₄は、上記式IVについて定義されたとおりであり;
R₁は、１回以上存在する場合、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、アミノアルキル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから独立して選択され、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、アミノアルキル、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;
R₂は、H、ハロ、C_1〜5アルキル、C_1〜5アルケニル、またはC_1〜5アルキニルであり;
o領域、p領域、およびq領域の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されている。

And a pharmaceutically acceptable salt and solvate thereof, in Formula IVb4:
Y and R ₆ are as defined for formula IVb above;
o, p, q, and Y ₄ are as defined for Formula IV above;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₂ is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl;
Any methylene group in the o, p, and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. .

  In some embodiments, the present invention provides compounds of formula IVb5

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IVb5において:
YおよびR₆は、上記式IVbについて定義されたとおりであり;
o、p、およびqは、上記式IVについて定義されたとおりであり;
R₁およびR₅は、一方または両方が１回以上存在する場合、各々独立して、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、アミノアルキル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから選択され、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、アミノアルキル、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;
R₃およびR₄は各々独立して、H、ハロ、またはC_1〜4アルキルであるか、あるいはR₃およびR₄は、これらが結合している炭素と一緒になって、シクロプロピル環またはシクロブチル環を形成し;そして
o領域、p領域、およびq領域の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されている。

And a pharmaceutically acceptable salt and solvate thereof, in Formula IVb5:
Y and R ₆ are as defined for formula IVb above;
o, p, and q are as defined for Formula IV above;
R ₁ and R ₅ , when one or both are present more than once, are each independently halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalo Selected from methyl, C-carboxy, O-carboxy, sulfonamido, amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amido, amino, aminoalkyl, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₃ and R ₄ are each independently H, halo, or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which they are attached, a cyclopropyl ring or Forming a cyclobutyl ring; and
Any methylene group in the o, p, and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. .

  In some embodiments, the present invention provides compounds of formula IVb6

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IVb6において:
YおよびR₆は、上記式IVbについて定義されたとおりであり;
o、p、およびqは、上記式IVについて定義されたとおりであり;
R₁およびR₅は、一方または両方が１回以上存在する場合、各々独立して、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、アミノアルキル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから選択され、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、アミノアルキル、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;
R₂は、H、ハロ、C_1〜5アルキル、C_1〜5アルケニル、またはC_1〜5アルキニルであり;そして
o領域、p領域、およびq領域の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されている。

And the pharmaceutically acceptable salts and solvates thereof, in Formula IVb6:
Y and R ₆ are as defined for formula IVb above;
o, p, and q are as defined for Formula IV above;
R ₁ and R ₅ , when one or both are present more than once, are each independently halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalo Selected from methyl, C-carboxy, O-carboxy, sulfonamido, amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amido, amino, aminoalkyl, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₂ is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl; and
Any methylene group in the o, p, and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. .

  In some embodiments, the present invention provides compounds of formula IVb7

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IVb7において:
YおよびR₆は、上記式IVaについて定義されたとおりであり;
o、p、およびqは、上記式IVについて定義されたとおりであり;
R₁およびR₅は、一方または両方が１回以上存在する場合、各々独立して、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、アミノアルキル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから選択され、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、アミノアルキル、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;
R₃およびR₄は各々独立して、H、ハロ、またはC_1〜4アルキルであるか、あるいはR₃およびR₄は、これらが結合している炭素と一緒になって、シクロプロピル環またはシクロブチル環を形成し;
o領域、p領域、およびq領域の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;そして
S、T、U、およびVは、炭素または窒素であり、ただし、S、T、U、およびVのうちの少なくとも１つは窒素であり、そしてS、T、U、またはVが窒素である場合、この窒素上に置換基は存在しない。

And the pharmaceutically acceptable salts and solvates thereof, in Formula IVb7:
Y and R ₆ are as defined for formula IVa above;
o, p, and q are as defined for Formula IV above;
R ₁ and R ₅ , when one or both are present more than once, are each independently halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalo Selected from methyl, C-carboxy, O-carboxy, sulfonamido, amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amido, amino, aminoalkyl, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₃ and R ₄ are each independently H, halo, or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which they are attached, a cyclopropyl ring or Forming a cyclobutyl ring;
Any methylene group in the o, p, and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. ; And
S, T, U, and V are carbon or nitrogen, provided that at least one of S, T, U, and V is nitrogen and S, T, U, or V is nitrogen If present, there are no substituents on this nitrogen.

  In some embodiments, the present invention provides compounds of formula IVb8

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IVb8において:
YおよびR₆は、上記式IVbについて定義されたとおりであり;
o、p、およびqは、上記式IVについて定義されたとおりであり;
R₁は、１回以上存在する場合、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、アミノアルキル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから独立して選択され、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、アミノアルキル、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;
R₂は、H、ハロ、C_1〜5アルキル、C_1〜5アルケニル、またはC_1〜5アルキニルであり;
o領域、p領域、およびq領域の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;そして
S、T、U、およびVは、炭素または窒素であり、ただし、S、T、U、およびVのうちの少なくとも１つは窒素であり、そしてS、T、U、またはVが窒素である場合、この窒素上に置換基は存在しない。

And the pharmaceutically acceptable salts and solvates thereof, in Formula IVb8:
Y and R ₆ are as defined for formula IVb above;
o, p, and q are as defined for Formula IV above;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₂ is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl;
Any methylene group in the o, p, and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. ; And
S, T, U, and V are carbon or nitrogen, provided that at least one of S, T, U, and V is nitrogen and S, T, U, or V is nitrogen If present, there are no substituents on this nitrogen.

  In some embodiments, the present invention provides compounds of formula IVc

の化合物、ならびにその薬学的に受容可能な塩および溶媒和物を提供し、式IVcにおいて:
Yは、3-ピリジニルまたは4-ピリジニルであり、必要に応じて、式IについてのYについて定義されたように置換されており;
Y₂、o、p、およびqは、上記式IVについて定義されたとおりであり;
R₁およびR₅は、一方または両方が１回以上存在する場合、各々独立して、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、アミノアルキル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから選択され、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、アミノアルキル、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されており;
R₆は、１回以上存在する場合、ハロ、C_1〜5アルキル、ニトロ、シアノ、C_1〜5アルコキシ、C-アミド、N-アミド、トリハロメチル、C-カルボキシ、O-カルボキシ、スルホンアミド、アミノ、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、およびスルフィニルから独立して選択され;そして
o領域、p領域、およびq領域、またはY₂の任意のメチレン基は独立して、C_1〜4アルキル、ハロ、C_1〜4ハロアルキル、またはC₃もしくはC₄シクロアルキルで必要に応じて置換されており;そして
ただし、Y₂が-C(=O)N(H)-である場合、Y₄は存在する。

And the pharmaceutically acceptable salts and solvates thereof, in Formula IVc:
Y is 3-pyridinyl or 4-pyridinyl, optionally substituted as defined for Y for formula I;
Y ₂ , o, p, and q are as defined for Formula IV above;
R ₁ and R ₅ , when one or both are present more than once, are each independently halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalo Selected from methyl, C-carboxy, O-carboxy, sulfonamido, amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amido, amino, aminoalkyl, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₆ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide Independently selected from, amino, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl; and
o-region, p-region, and q-region, or any methylene group in Y ₂ is independently C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl as required Substituted, and Y ₄ is present when Y ₂ is —C (═O) N (H) —.

In some embodiments of each compound of Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, and Id, Z ₀ is a carbocycle, cycloalkyl, cycloalkenyl, heterocycle, heterocycle Cyclonoyl, aryl, heteroaryl, carbocycloalkyl, heterocyclylalkyl, arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, or arylalkynyl, wherein each of the above groups is alkyl, alkylene , Alkenyl, alkenylene, alkynyl, carbocycle, cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl, halo, hydro, hydroxyl, alkoxy, alkynyloxy, cycloalkyloxy, heterocyclooxy, aryloxy, heteroary Oxy, arylalkoxy, heteroarylalkoxy, mercapto, alkylthio, arylthio, arylalkyl, heteroarylalkyl, heteroarylalkenyl, arylalkynyl, haloalkyl, aldehyde, thiocarbonyl, heterocyclonoyl, O-carboxy, C-carboxy, carboxylic acid Ester, C-carboxy salt, carboxyalkyl, carboxyalkenylene, carboxyalkyl salt, carboxyalkoxy, carboxyalkoxyalkanoyl, amino, aminoalkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C- Amide, N-amide, aminothiocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, cyano, nitrile, cyanato, isocyanato, thio Cyanato, isothiocyanato, sulfinyl, sulfonyl, sulfonamido, aminosulfonyl, amino sulfonyloxy, sulfonamido carbonyl, alkanoylamino sulfonyl is substituted at least once with a trihalomethyl sulfonyl or trihalomethyl sulfonamide.

In some embodiments of each compound of Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, and Id, Z ₀ is an optionally substituted aryl, optionally It is selected from substituted heteroaryl, optionally substituted carbocycle, and optionally substituted heterocycle.

In some embodiments of each compound of Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, and Id, Z ₀ is aryl, independently and optionally substituted. Alkyl, N-amide, optionally substituted carbocycle, optionally substituted carbocycloamino, optionally substituted heterocycle, optionally substituted heterocycloalkyl, required Optionally substituted heterocycloamino, optionally substituted heterocyclonoyl, optionally substituted aryl, optionally substituted heteroaryl, halo, hydro, hydroxyl, optionally Substituted hydroxyalkyl, optionally substituted haloalkoxy, optionally substituted alkoxy, optionally substituted aminoalkoxy, optionally substituted hete Cycloalkoxy, optionally substituted haloalkyl, optionally substituted amino, optionally substituted aminoalkyl, nitro, optionally substituted C-amide, optionally substituted Optionally substituted one or more times with N-amide, cyano, or optionally substituted sulfonamides.

In some embodiments of each compound of Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, and Id, Z ₀ is a first aryl substituted with a second aryl. Wherein each of the first aryl and the second aryl is independently N-amide, optionally substituted carbocycle, carbocycloamino, optionally substituted heterocycle, heterocyclo Alkyl, heterocycloamino, heterocyclonoyl, halo, hydro, hydroxyl, hydroxyalkyl, haloalkoxy, alkoxy, aminoalkoxy, heterocycloalkoxy, haloalkyl, optionally substituted amino, aminoalkyl, nitro, optionally Optionally substituted one or more times with optionally substituted C-amide, optionally substituted N-amide, cyano, or sulfonamide. In some of such embodiments, the first aryl is phenyl. In some of such embodiments, the second aryl is phenyl. In some of such embodiments, both the first aryl and the second aryl are phenyl.

In some embodiments of each compound of Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, and Id, Z ₀ is an optionally substituted phenyl, optionally Substituted 2-pyridinyl, optionally substituted 3-pyridinyl, optionally substituted 4-pyridinyl, optionally substituted pyrimidine, optionally substituted pyrazine, optionally Optionally substituted pyrazole, optionally substituted thiophene, optionally substituted ortho-biphenyl, optionally substituted 1-naphthalenyl, optionally substituted 2-naphthalenyl, optionally An optionally substituted quinazoline, an optionally substituted benzothiadiazine, an optionally substituted indole, and an optionally substituted pyridopyrimidine.

  In some embodiments of each compound of Formula II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, and IId1, Z Is hydro, alkyl, N-amide, optionally substituted carbocycle, carbocycloamino, optionally substituted heterocycle, heterocycloalkyl, heterocycloamino, heterocyclonoyl, optionally Substituted aryl, optionally substituted heteroaryl, halo, hydro, hydroxyl, hydroxyalkyl, haloalkoxy, alkoxy, aminoalkoxy, heterocycloalkoxy, haloalkyl, optionally substituted amino, aminoalkyl, Nitro, optionally substituted C-amide, optionally substituted N-amide, cyano, or sulfonamide.

  In some embodiments of each compound of Formula II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, and IId1, Z Is hydro, optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrimidine, optionally substituted pyrazole, optionally substituted piperidine, required Optionally substituted morpholine, optionally substituted piperazine, optionally substituted thiophene, optionally substituted imidazole, optionally substituted oxadiazole, optionally Substituted oxazole, optionally substituted isoxazole, optionally substituted cyclohexyl, optionally substituted cyclohexylamino, optionally substituted Piperidinylamino, or optionally substituted pyrrolidine.

Some of the compounds of each of formulas IIa3, IIa4, IIb4, IIb5, IIb6, IIb7, IIc1, IId1, IIIa3, IIIa4, IIIa5, IIIa6, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, and IIIc In embodiments, R ₁ is absent or present once, twice, three times, or four times. In some embodiments of each compound of formula IIIa6, IIIb8, and IIIb11, R ₁ is present 5 times.

Formula IIa3, IIa4, IIb4, IIb5, IIb6, IIb7, IIc1, IId1, IIIa3, IIIa4, IIIa5, IIIa6, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IVa3, IVa3, IVa3 , IVb4, IVb5, IVb7, and IVc, in some embodiments, R ₁ is an electron withdrawing group, such as, but not limited to, halo, trihalomethyl, nitro, cyano, C-carboxy, O-carboxy, C-amide, and N-amide.

In some embodiments of each compound of Formula IIIa4, IIIb5, IVa4, and IVb4, Y ₄ is absent, R ₁ is present 2 or 3 times, and each instance of R ₁ is an electron withdrawing Sex group.

Formula IIa3, IIa4, IIb4, IIb5, IIb6, IIb7, IIc1, IId1, IIIa3, IIIa4, IIIa5, IIIa6, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IVa3, IVa3, IVa3 , IVb4, IVb5, IVb7, and IVc, in some embodiments, R ₁ is C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, Or selected from alkylthio, each further substituted with heterocyclo, cycloalkyl, or amino.

In some embodiments of each compound of Formula IIIa5, IIIb7, IIIb10, and IIIc, R ₅ is absent or present once, twice, three times, four times, or five times. In some embodiments of each compound of formula IIIa5, IIIb7, IIIb8, IIIb9, IIIb10, IIIc, IVa5, IVb5, IVb7, and IVc, R ₅ is C _1-5 alkyl, C _1-5 alkoxy, C Selected from -amide, N-amido, amino, aminoalkyl, or alkylthio, each further substituted with heterocyclo, cycloalkyl, or amino.

Formula IIa3, IIa4, IIb4, IIb5, IIb6, IIb7, IIc1, IId1, IIIa3, IIIa4, IIIa5, IIIa6, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IVa3, IVa4, IVa5, IVb In some embodiments of each compound of, IVb4, IVb5, IVb7, and IVc, R ₁ is:

から選択され、ここでtは、0、1、2、3、または4であり、Wは、N(H)、O、C(H)₂、またはSであり、そしてR_aおよびR_bは各々独立して、ヒドロ、C_3〜6シクロアルキル、またはC_1〜6アルキルであるか、あるいはR_aおよびR_bは、これらの間の連結窒素原子と一緒になって、アゼチジン、ピロリジン、またはピペリジンを形成する。

Where t is 0, 1, 2, 3, or 4, W is N (H), O, C (H) ₂ , or S, and R _a and R _b are Each independently hydro, C _3-6 cycloalkyl, or C _1-6 alkyl, or R _a and R _b together with a linking nitrogen atom between them, azetidine, pyrrolidine, or Form piperidine.

In some embodiments of each compound of Formula IIIa5, IIIb7, IIIb8, IIIb9, IIIb10, IIIc, IVa5, IVb5, IVb7, and IVc, R ₅ is:

から選択され、ここでtは、0、1、2、3、または4であり、Wは、N(H)、O、C(H)₂、またはSであり、そしてR_aおよびR_bは各々独立して、ヒドロ、C_3〜6シクロアルキル、またはC_1〜6アルキルであるか、あるいはR_aおよびR_bは、これらの間の連結窒素原子と一緒になって、アゼチジン、ピロリジン、またはピペリジンを形成する。

Where t is 0, 1, 2, 3, or 4, W is N (H), O, C (H) ₂ , or S, and R _a and R _b are Each independently hydro, C _3-6 cycloalkyl, or C _1-6 alkyl, or R _a and R _b together with a linking nitrogen atom between them, azetidine, pyrrolidine, or Form piperidine.

In some embodiments of each compound of formula IIIa5, IIIb7, IIIb8, IIIb9, IIIb10, IIIc, IVa5, IVb5, IVb7, and IVc, R ₁ and / or R ₅ are present and on the biphenyl ring, Less than:

に示されるように位置し、ここでR₁およびR₅の各々は、以下:

Where R ₁ and R ₅ are each:

から選択され、ここでtは、0、1、2、3、または4であり、Wは、N(H)、O、C(H)₂、またはSであり、そしてR_aおよびR_bは各々独立して、ヒドロ、C_3〜6シクロアルキル、またはC_1〜6アルキルであるか、あるいはR_aおよびR_bは、これらの間の連結窒素と一緒になって、アゼチジン、ピロリジン、またはピペリジンを形成し;ただし、R₁とR₅との両方がビフェニル環上に存在する場合、R₁は、C_1〜4ハロアルキル(例えば、トリフルオロメチル)またはハロ(例えば、クロロ)である。

Where t is 0, 1, 2, 3, or 4, W is N (H), O, C (H) ₂ , or S, and R _a and R _b are Each independently hydro, C _3-6 cycloalkyl, or C _1-6 alkyl, or R _a and R _b together with a linking nitrogen between them, azetidine, pyrrolidine, or piperidine Provided that when both R ₁ and R ₅ are present on the biphenyl ring, R ₁ is C _1-4 haloalkyl (eg, trifluoromethyl) or halo (eg, chloro).

Formulas Ia2, Ib2, Id, IIa2, IIa4, IIb2, IIb5, IId, IId1, IIIa2, IIIa4, IIIa6, IIIb2, IIIb5, IIIb5IIIb8, IIIb11, IVa2, IVa4, IVa6, IVb2, IVb4, IVb6, and IVb8, respectively In some embodiments of the compound, R ₂ is hydrogen or cyclopropyl. In some of such embodiments, R ₂ is hydrogen.

  In some embodiments of each compound of formula I, II, III, and IV, R in Y is hydrogen.

In some embodiments of each compound of formula I, II, III, and IV, R is hydrogen in Y ₁ .

In some embodiments of each compound of formula I, II, III, and IV, R is hydrogen at Y ₂ .

Formulas Ib1, Ic, IIb1, IIb4, IIc, IIc1, IIIa1, IIIa3, IIIa5, IIIb1, IIIb4, IIIb7, IIIb8, IIIb9, IIIb10, IIIc, IVa1, IVa3, IVa5, IVb1, IVb3, IVb5, and IVb7 In some embodiments of the compound, both R ₃ and R ₄ are hydrogen, or both are fluoro. In some of such embodiments, both R ₃ and R ₄ are hydrogen.

Formula Ib, Ib1, Ib2, Ib3, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc , IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, in some embodiments, R ₆ is absent or 1, 2, 3, Or it exists 4 times. In some of such embodiments, R ₆ is absent or is fluoro, methyl, or trifluoromethyl. In some such embodiments, R ₆ is absent.

  Of each compound of formula Ia, Ia1, Ia2, IIa, IIa1, IIa2, IIa3, IIa4, IIIa, IIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, and IVa6 In some embodiments, n is 4, 5, or 6. Of each compound of formula Ia, Ia1, Ia2, IIa, IIa1, IIa2, IIa3, IIa4, IIIa, IIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, and IVa6 In some embodiments, n is 4. Of each compound of formula Ia, Ia1, Ia2, IIa, IIa1, IIa2, IIa3, IIa4, IIIa, IIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, and IVa6 In some embodiments, n is 5. Of each compound of formula Ia, Ia1, Ia2, IIa, IIa1, IIa2, IIa3, IIa4, IIIa, IIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, and IVa6 In some embodiments, n is 6. Of each compound of formula Ia, Ia1, Ia2, IIa, IIa1, IIa2, IIa3, IIa4, IIIa, IIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, and IVa6 In some embodiments, any methylene group in the n region is optionally substituted with fluoro or methyl. Of each compound of formula Ia, Ia1, Ia2, IIa, IIa1, IIa2, IIa3, IIa4, IIIa, IIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, and IVa6 In some embodiments, any methylene group in the n region is all fully saturated.

  Formula III, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc In some embodiments of each compound, o is 0. Formula IIIIII, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc In some embodiments of each compound, o is 1. Formula III, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc In some embodiments of each compound, o is 2. Formula III, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc In some embodiments of each compound, any methylene group in the o region is optionally substituted with fluoro or methyl. Formula III, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc In some embodiments of each compound, any methylene group in the o region is all fully saturated.

  Formula III, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc In some embodiments of each compound, p is 0. Formula III, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc In some embodiments of each compound, p is 1. Formula III, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc In some embodiments of each compound, p is 2. Formula III, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc In some embodiments of each compound, any methylene group in the p region is optionally substituted with fluoro or methyl. Formula III, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc In some embodiments of each compound, any methylene group in the p region is all fully saturated.

  Formula III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2 In some embodiments of each of the compounds Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, q is 0. Formula III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2 In some embodiments of each of the compounds Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, q is 1. Formula III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2 In some embodiments of each of the compounds Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, q is 2. Formula III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2 In some embodiments of each compound of Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, any methylene group in the q region is: Optionally substituted with fluoro or methyl. Formula III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2 In some embodiments of each compound of Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, any methylene group in the q region is: All are fully saturated.

  In some embodiments of each compound of formula Ib3, IIb3, IIb6, IIIb3, IIIb6, and IIIb9, u is 0. In some embodiments of each compound of formula Ib3, IIb3, IIb6, IIIb3, IIIb6, and IIIb9, u is 1. In some embodiments of each compound of formula Ib3, IIb3, IIb6, IIIb3, IIIb6, and IIIb9, when u is 1, the methylene group in the u region is substituted with fluoro or methyl. In some embodiments of each compound of Formula Ib3, IIb3, IIb6, IIIb3, IIIb6, and IIIb9, when u is 1, the methylene group in the u region is fully saturated.

  Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc In some embodiments of each of the compounds of, IIc1, IId, and IId1, any methylene groups are all fully saturated.

  In some embodiments of each compound of formula I, II, III, and IV, Y is phenyl. In some embodiments of each compound of formula I, II, III, and IV, Y is 2-pyridinyl. In some of any such embodiments, Y is unsubstituted or once, twice, three times, or four as defined for Y for formulas I and II. Has been replaced twice. Further, in some such embodiments, the optional substituent for Y is halo (eg, fluoro, etc.), methyl, nitro, cyano, trihalomethyl, methoxy, amino, hydroxyl, or mercapto.

Formula I, II, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa , IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, in some embodiments, Y is 3-pyridinyl It is. Formula I, II, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa , IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, in some embodiments, Y is 4-pyridinyl It is. Formula I, II, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa In some embodiments of each of the following compounds: Y, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc Or is substituted once, twice, three times, or four times as defined for Y for formula I. Formula I, II, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa Optional substitution of Y in some embodiments of each of the following compounds:, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc The group is halo (eg, fluoro, etc.), methyl, nitro, cyano, trihalomethyl, methoxy, amino, hydroxyl, or mercapto. Formula I, II, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa In some embodiments of each of the following compounds: Ya, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc It is 3-pyridinyl or 3-pyridinyl substituted with NH ₂ in the 4-position.

In some embodiments of each compound of Formula II, IIa, IIa2, IIb, IIb2, and IId, any substituent on Z and / or Y ₃ is such that Y ₃ is an electron deficient aryl ring or an electron deficiency Selected to be a heteroaryl ring.

In some embodiments of each compound of Formula IIa4, IIb5, and IId1, Z and / or R ₁ are selected such that the phenyl ring is electron deficient.

In some embodiments of each compound of Formula III, IIIa, IIIa2, IIIb, IIIb2, IV, IVa, IVa2, IVb, and IVb2, Y ₄ is absent and any substituents on Y ₃ are , Y ₃ is selected to be electron deficient.

In some embodiments of each compound of Formula I, Ic, Id, II, IIc, IIc1, IId, IId1, III, and IV, Y ₁ is a divalent carbocycle, divalent heterocycle, di Divalent phenyl or divalent heteroaryl, wherein any ring carbon atom is independently halo, C _1-5 alkyl, nitro, cyano, trihalomethyl, C _1-5 alkoxy, C-amide, N -Optionally substituted with amide, sulfonamido, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl.

In some embodiments of each compound of Formula I, Ic, Id, II, IIc, IIc1, IId, IId1, III, and IV, Y ₁ is divalent cyclohexyl, divalent piperidinyl, divalent Phenyl, divalent pyridinyl, divalent pyrimidinyl, divalent thiophenyl, and divalent triazolyl, wherein any ring carbon atom is independently halo, C _1-5 alkyl, nitro, cyano, trihalo Further substituted with methyl, C _1-5 alkoxy, C-amide, N-amide, sulfonamido, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl as required.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —OCH ₂ -, -SCH _2- , -N (R) CH _2- , -CH ₂ O-, -CH ₂ S-, -CH ₂ N (R)-, -SO ₂ N (R)-, -N (R ) SO _2- , -C _1-4 alkylene-SO ₂ N (R)-, -C _1-4 alkylene-N (R) SO _2- , -SO ₂ N (R) -C _1-4 alkylene-, -N (R) SO ₂ -C _1~4 alkylene -, - C _{1 to 4} alkylene -OC _{1 to 4} alkylene -, - OC _{1 to 4} alkylene -, - C _{1 to 4} alkylene -O -, - SC _{1 to 4} alkylene -, - C _{1 to 4} alkylene -S _-, - C _1~4 alkylene -SC _{1 to 4} alkylene -, - N (R) -C 1~4 alkylene -, - C _{1 to 4} alkylene -N (R)-, or -C _1-4 alkylene-N (R) -C _1-4 alkylene-, where R is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —S ( = O) ₂ CH _2- , -S (= O) CH _2- , -CH ₂ O-, -CH ₂ S-, -CH ₂ N (R)-, -CH ₂ S (= O) _2- , -CH ₂ S (= O)-, -C (= O) O-, -OC (= O)-, -SO ₂ N (R)-, -N (R) SO _2- , -OC _1-4 alkylene -N (R) C (= O ) -, - C 1~4 alkylene _{-S (= O) 2 -,} - C 1~4 alkylene -S (= O) -, - S (= O) 2 - C _1-4 alkylene-, -S (= O) -C _1-4 alkylene-, -C _1-4 alkylene-SO ₂ N (R)-, -C _1-4 alkylene-N (R) SO _2- , -SO ₂ N (R) -C _1-4 alkylene-, -N (R) SO ₂ -C _1-4 alkylene-, -C _1-4 alkylene-OC _1-4 alkylene-, -OC _1-4 alkylene -, - C _{1 to 4} alkylene -O _-, - C _1~4 alkylene -S _-, - C _1~4 alkylene -SC _{1 to 4} alkylene -, - C _{1 to 4} alkylene -N (R) -, -C _{1 to 4} alkylene -N (R) _-C 1~4 alkylene -, - C _{1 to 4} alkylene _-C (= O) -OC 1~4 alkylene -, - C _{1 to 4} alkylene -OC (= O) _-C 1~4 alkylene -, - C _{1 to 4} alkylene -C (= O) -N (R ) -C 1~4 alkylene -, or -C _{1 to 4} alkylene -N (R ) —C (═O) —C _1-4 alkylene-, wherein R is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —SCH ₂ — It is.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —N (R ) CH ₂ -, wherein R is, H, halo, C _{1 to 5} alkyl, C _{1 to 5} alkenyl or C _{1 to 5} alkynyl,.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —N (R ) C (═O) —, wherein R is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —C (= O) N (R) —, where R is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —S (= O) ₂ CH _2- .

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —S (= O) CH ₂ - a.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —CH ₂ S -That's it.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —CH ₂ N (R) —, where R is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —CH ₂ S (= O) _2- .

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —CH ₂ S (= O)-.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —C (= O) O-.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —OC (═ O)-.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —N (R ) SO ₂ —, where R is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is ethylene.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is propylene.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is n-butylene is there.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —OC _{1 to 4} alkylene -N (R) C (= O ) - , wherein R is, H, halo, C _{1 to 5} alkyl, C _{1 to 5} alkenyl or C _{1 to 5} alkynyl,.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —OC _{1 to 4} alkylene -C (= O) N (R ) - , wherein R is, H, halo, C _{1 to 5} alkyl, C _{1 to 5} alkenyl or C _{1 to 5} alkynyl,.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —N (R ₎ C (= O) -C 1~4 alkylene -O-, wherein R is, H, halo, C _{1 to 5} alkyl, C _{1 to 5} alkenyl or C _{1 to 5} alkynyl,.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —C (= O) N (R) —C _1-4 alkylene-O—, wherein R is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —C _{1 4} alkylene-S (═O) ₂ —.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —C _{1 4} alkylene-S (= O)-.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —S (= O) ₂ -C _{1 to 4} alkylene - a.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —S (= O) —C _1-4 alkylene.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —C _{1 4} alkylene -SO ₂ N (R) -, wherein R is, H, halo, C _{1 to 5} alkyl, C _{1 to 5} alkenyl or C _{1 to 5} alkynyl,.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —C _{1 4} alkylene -N (R) SO ₂ -, wherein R is, H, halo, C _{1 to 5} alkyl, C _{1 to 5} alkenyl or C _{1 to 5} alkynyl,.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —SO ₂ N (R) —C _1-4 alkylene-, wherein R is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —N (R ) SO ₂ -C _{1 to 4} alkylene -, wherein R is, H, halo, C _{1 to 5} alkyl, C _{1 to 5} alkenyl or C _{1 to 5} alkynyl,.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —C _{1 4} alkylene-OC _1-4 alkylene.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —OC _{1 to 4} alkylene-.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —C _{1 4} alkylene-O-.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —SC ₁ — ₄ alkylene-.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —C _{1 4} alkylene-S-.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —C _{1 4} alkylene-SC _1-4 alkylene.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —N (R ) -C _{1 to 4} alkylene -, wherein R is, H, halo, C _{1 to 5} alkyl, C _{1 to 5} alkenyl or C _{1 to 5} alkynyl,.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —C _{1 4} alkylene -N (R) -, wherein R is, H, halo, C _{1 to 5} alkyl, C _{1 to 5} alkenyl or C _{1 to 5} alkynyl,.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —C _{1 4} alkylene -N (R) -C _{1 to 4} alkylene -, and wherein R is, H, halo, C _{1 to 5} alkyl, C _{1 to 5} alkenyl or C _{1 to 5} alkynyl,.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —C _{1 4} alkylene _-C (= O) -OC 1~4 alkylene - a.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —C _{1 4} alkylene _-OC (= O) -C 1~4 alkylene - a.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —C _{1 4} alkylene -C (= O) -N (R ) -C 1~4 alkylene -, wherein R is, H, halo, C _{1 to 5} alkyl, C _{1 to 5} alkenyl or C _{1 to 5} alkynyl, It is.

In some embodiments of each compound of Formula I, Ia, Ib, II, IIa, IIb, IIb7, III, IIIa, IIIb, IIIc, IV, IVa, IVb, and IVc, Y ₂ is —C _{1 4} alkylene -N (R) -C (= O ) -C 1~4 alkylene -, wherein R is, H, halo, C _{1 to 5} alkyl, C _{1 to 5} alkenyl or C _{1 to 5} alkynyl, It is.

Formula II, IIa, IIa1, IIa2, IIb, IIb1, IIb2, IIb3, IIc, IId, III, IIIa, IIIa1, IIIa2, IIIb, IIIb1, IIIb2, IIIb3, IV, IVa, IVa1, IVa2, IVb, IVb1, and In some embodiments of each compound of IVb2, Y ₃ is phenyl, pyridinyl, pyrimidinyl, divalent phenyl, divalent pyridinyl, or divalent pyrimidinyl, wherein any ring carbon is independently And independently in the case of a divalent ring, further halo, C _1-5 alkyl, nitro, cyano, trihalomethyl, C _1-5 alkoxy, C-amide, N-amide, sulfonamide, amino, Optionally substituted with aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl, where C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, and alkylthio are Each need Where appropriate, it is substituted with heterocyclo, cycloalkyl, or amino.

Formula III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVb, IVb1, IVb2, IVb3, and IVb4 In some embodiments of each compound, Y ₄ is optionally present and when present is an aryl, heteroaryl, carbocycle, or heterocycle, wherein any ring carbon atom is independently Halo, C _1-5 alkyl, nitro, cyano, trihalomethyl, C _1-5 alkoxy, C-amide, N-amide, sulfonamido, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, sulfinyl are optionally substituted, wherein C _{1 to 5} alkyl, C _{1 to 5} alkoxy, C-amido, N- amido, amino, and alkylthio, each optionally, heterocyclo, cycloalkyl or a, It has been replaced with Roh.

Formula III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVb, IVb1, IVb2, IVb3, and IVb4 In some embodiments of each compound, Y ₄ is present.

Formula III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVb, IVb1, IVb2, IVb3, and IVb4 In some embodiments of each compound, Y ₄ is phenyl, morpholino, piperazinyl, oxydiazolyl, oxazolyl, pyrrolidinyl, thienyl (thiophenyl), benzo [b] thienyl, naphtho [2,3-b] thienyl, Thianthrenyl, furyl (furanyl), isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, pyrrolyl (e.g. 2H-pyrrolyl), pyrroline, imidazolyl, imidazolidinyl, pyrazolyl, pyridyl (pyridinyl) (e.g. 2-pyridyl, 3 -Pyridyl and 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, Danazolyl, purinyl, 4H-quinolidinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, isothiazonoyl, thiazonoyl , Isoxazolyl, furazanyl, phenoxazinyl, 1,4-dihydroquinoxaline-2,3-dione, 7-aminoisocoumarin, pyrido [1,2-a] pyrimidin-4-one, pyrazolo [1,5-a] pyrimidinyl ( For example, pyrazolo [1,5-a] pyrimidin-3-yl), 1,2-benzisoxazol-3-yl, benzimidazolyl, 2-oxoindolyl, 2-oxobenzimidazolyl, triazine, dioxoanyl, dithianyl , Thiomorpholinyl, trithia Le, cyclobutyl, cyclohexyl, cycloheptyl, group selected from cyclooctyl, and cyclohexenyl, where each of these groups being optionally substituted as defined for Y ₄ in formula III Yes.

Formula III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVb, IVb1, IVb2, IVb3, and IVb4 In some embodiments of each compound, Y ₄ is selected from phenyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, pyrimidinyl, morpholino, piperazinyl, oxydiazolyl, oxazolyl, pyrrolidinyl, imidazolyl, and piperidinyl. Wherein each of these groups is optionally substituted as defined for Y ₄ in Formula III.

Formula III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVb, IVb1, IVb2, IVb3, and IVb4 In some embodiments of each compound, Y ₄ is:

から選択される基であり、ここでVは、NまたはC(H)であり、そしてWは、N、O、C(H)、またはSであり、ここで任意の環原子は独立して、ハロ、C_1〜5アルキル、ニトロ、シアノ、トリハロメチル、C_1〜5アルコキシ、C-アミド、N-アミド、スルホンアミド、アミノ、アミノスルホニル、ヒドロキシル、メルカプト、アルキルチオ、スルホニル、スルフィニルで必要に応じて置換されており、ここでC_1〜5アルキル、C_1〜5アルコキシ、C-アミド、N-アミド、アミノ、およびアルキルチオは、各々必要に応じて、ヘテロシクロ、シクロアルキル、またはアミノで置換されている。

Wherein V is N or C (H), and W is N, O, C (H), or S, wherein any ring atom is independently , halo, C _{1 to 5} alkyl, nitro, cyano, trihalomethyl, C _{1 to 5} alkoxy, C-amido, N- amido, sulfonamido, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, needs sulfinyl Optionally substituted, where C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino Has been.

  In some embodiments of each compound of formula Ib, IIb, IIIb, IIIb10, IIIb11, IIIc, IVb, IVb7, IVb8, and IVc, at least two of S, T, U, and V are nitrogen is there. In some embodiments of each compound of Formula Ib, IIb, IIIb, IIIb10, IIIb11, IIIc, IVb, IVb7, IVb8, and IVc, only S is nitrogen. In some embodiments of each compound of Formula Ib, IIb, IIIb, IIIb10, IIIb11, IIIc, IVb, IVb7, IVb8, and IVc, only T is nitrogen. In some embodiments of each compound of Formula Ib, IIb, IIIb, IIIb10, IIIb11, IIIc, IVb, IVb7, IVb8, and IVc, only U is nitrogen. In some embodiments of each compound of Formula Ib, IIb, IIIb, IIIb10, IIIb11, IIIc, IVb, IVb7, IVb8, and IVc, only V is nitrogen. In some embodiments of each compound of Formula Ib, IIb, IIIb, IIIb10, IIIb11, IIIc, IVb, IVb7, IVb8, and IVc, T and V are nitrogen. In some embodiments of each compound of Formula Ib, IIb, IIIb, IIIb10, IIIb11, IIIc, IVb, IVb7, IVb8, and IVc, S and U are nitrogen.

  Formula III, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and In some embodiments of each compound of IVc, Y is unsubstituted 3-pyridinyl and q is 1.

  Formula III, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and In some embodiments of each compound of IVc, Y is unsubstituted 3-pyridinyl, q is 1 and p is 0.

  Formula III, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and In some embodiments of each compound of IVc, Y is unsubstituted 3-pyridinyl, q is 1, p is 0, and o is 0.

  Formula III, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and In some embodiments of each compound of IVc, Y is unsubstituted 3-pyridinyl, q is 1, p is 0, and o is 0.

Formula III, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and In some embodiments of each compound of IVc, Y is unsubstituted 3-pyridinyl, q is 1, p is 0, o is 0, and R ₆ is absent.

  In some embodiments of each compound of Formula III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, and IVa6, Y is unsubstituted 3 -Pyridinyl and q is 1.

  In some embodiments of each compound of Formula III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, and IVa6, Y is unsubstituted 3 -Pyridinyl, q is 1 and n is 4, 5 or 6.

  In some embodiments of each compound of Formula III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, and IVa6, Y is unsubstituted 3 -Pyridinyl, q is 1, n is 4, 5, or 6, and the methylene groups of n and q are all fully saturated.

In some embodiments of each compound of Formula Ib, Ib1, Ib2, Ib3, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, and IIb7, R ₆ and R ₇ are absent.

In some embodiments of each compound of formula Ib, Ib1, Ib2, Ib3, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, and IIb7, R ₆ and R ₇ are absent and any The methylene group is fully saturated.

In some embodiments of each compound of Formula Ia, Ia1, Ia2, IIa, IIa1, IIa2, IIa3, and IIa4, n is 4, 5, or 6, and R ₇ is absent.

In some embodiments of each compound of Formula Ia, Ia1, Ia2, IIa, IIa1, IIa2, IIa3, and IIa4, n is 4, 5, or 6, R ₇ is absent, and optional The methylene group of is fully saturated.

  The compounds of the invention have the formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, as shown herein IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5 , IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and The compounds of IVc, and the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4, and any of these, include stereochemically isomeric forms thereof. The compounds of the present invention are also represented by the formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, as shown herein. IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, And pharmaceutically acceptable salts, prodrugs, N-oxide forms, quaternary amines, and solvates of compounds of IV and IVc, and compounds of Tables 1A and 1B, 2, 3A and 3B, and 4 To do.

  For therapeutic use, as shown herein, Formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5 , IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and The compounds of IVc and the salts of the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4 are specific salts whose counterions are pharmaceutically acceptable. However, non-pharmaceutically acceptable acid and base salts may also find use, for example, in the preparation or purification of pharmaceutically acceptable compounds. All salts, whether pharmaceutically acceptable or not, are within the scope of the present invention.

  Pharmaceutically acceptable addition salts, as described herein, have formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, as shown herein. Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, Pharmaceutically active non-toxic acid additions that the compounds of IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc and the compounds of Tables 1A and 1B, 2, 3A, and 3B, and 4 can form It is meant to encompass the salt form. These salts can have their base form, for example, an inorganic acid (eg, hydrohalic acid (eg, hydrochloric acid, and hydrobromic acid); sulfuric acid; nitric acid; and phosphoric acid); or an organic acid (eg, Acetic acid, propanoic acid, hydroxy-acetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, 2-hydroxy-1,2,3 -Propane tricarboxylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid etc.) It can be conveniently obtained by treating with an acid. Conversely, this salt can be converted to its free base form by treatment with alkali.

  Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, as shown herein, including acidic protons IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc And the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4 can be converted to their pharmaceutically active non-toxic metal or amine addition salts by treatment with appropriate organic and inorganic bases. Can be converted. Suitable base salt forms include, for example, ammonium salts, alkali metal salts and alkaline earth metal salts (eg, lithium, sodium, potassium, magnesium, and calcium salts), salts with organic bases (eg, Primary, secondary and tertiary aliphatic and aromatic amines (eg methylamine, ethylamine, propylamine, isopropylamine, four butylamine isomers, dimethylamine, diethylamine, diethanolamine, diethanolamine) Propylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline, benzathine, N-methyl-D-glucamine, 2-amino-2- (Hydro Shimechiru) -1,3-propanediol, hydrabamine) salts), as well as the amino acid (e.g., salts with such arginine and lysine). Conversely, this salt form can be converted to its free acid form by treatment with acid.

  The term addition salt also includes formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, as shown herein. IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5 , IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and Includes the hydrates and solvent addition forms that the compounds of IVc and the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4 can form. Examples of such forms are, for example, hydrates and alcohol solvates.

  The term “quaternary amine” as used herein refers to the formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, as shown herein. II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5 , IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2 , IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and compounds of Tables 1A and 1B, 2, 3A, and 3B, and 4, as shown herein, are represented by Formulas I, Ia Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, III b4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8 and IVc compounds and one of the compounds in Tables 1A and 1B, 2, 3A and 3B, and 4 with a basic nitrogen and an appropriate quaternizing agent (eg, optionally substituted) Specifies quaternary ammonium salts that can be formed by reaction with alkyl halides, aryl halides, or arylalkyl halides (eg, methyl iodide or benzyl iodide). Other reactants with good leaving groups, such as alkyl trifluoromethanesulfonate, alkyl methanesulfonate, and alkyl p-toluenesulfonate can also be used. Quaternary amines have a positively charged nitrogen. Pharmaceutically acceptable counterions include chloride ions, bromide ions, iodide ions, trifluoroacetate ions, and acetate ions. The selected counter ion can be introduced using an ion exchange resin.

  Formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, as shown herein IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8 , IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Table Pharmaceutically acceptable salts of the compounds 1A and 1B, 2, 3A and 3B, and 4 are exemplified by alkaline salts with inorganic acids and / or salts with organic acids known in the art. All salts are included. Further, pharmaceutically acceptable salts include inorganic base acid salts and organic base acid salts. These hydrates and solvates are also encompassed in the present invention. In addition, N-oxide compounds are also encompassed by the present invention.

  Formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, as shown herein IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8 , IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Table Compounds 1A and 1B, 2, 3A and 3B, and 4, and their N-oxides, addition salts, quaternary amines and some of the stereochemically isomeric forms are one or more chiral It is understood that the center can be included and can exist stereochemically as an isomeric form.

  The term “stereochemically isomeric form”, as used herein, has the formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, as indicated herein. Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, Compounds of IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and compounds of Tables 1A and 1B, 2, 3A and 3B, and 4, and their N-oxides, addition salts, fourth Defines all possible stereoisomers that can be taken by a primary amine or a physiologically functional derivative. Unless otherwise stated or indicated, the chemical designations of a compound describe a mixture of all possible stereochemically isomeric forms, these mixtures being as indicated herein. , Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, Compounds IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Tables 1A and 1B, 2, 3A, and 3B And all possible diastereomers and enantiomers of the basic molecular structure, as well as their N-oxides, salts, solvates or quaternary amines, and individual Each of the isomeric forms (substantially free of other isomers, ie with less than 10%, preferably less than 5%, especially 2% and most preferably less than 1% of other isomers) including. Specifically, the stereogenic center can have an R configuration or an S configuration, and a substituent on a divalent cyclic (partial) saturated group can have either a cis configuration or a trans configuration. A compound containing a double bond may have E or Z stereochemistry at this double bond. Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, as shown herein IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8 , IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Table The stereochemically isomeric forms of the compounds of 1A and 1B, 2, 3A and 3B, and 4 are fully intended to be included within the scope of the present invention.

  “N-oxide” refers to a compound of the formula I, Ia, Ia1, Ia2, Ib, Ib1, as shown herein, wherein one or several nitrogen atoms are oxidized to so-called N-oxides. Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, It is meant to encompass the compounds of IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and the compounds of Tables 1A and 1B, 2, 3A, and 3B, and 4.

  Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, as shown herein IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8 , IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Table Some of the compounds of 1A and 1B, 2, 3A and 3B, and 4 can also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.

In a preferred embodiment, a compound of the invention having an IC ₅₀ of less than about 100 nM, for example a table, as determined in a cytotoxicity assay as described in the following examples (i.e. cytotoxicity assays). Compounds listed in 1A and 1B and 3A and 3B are provided.

  Compounds of the present invention (e.g., formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, as shown herein, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, In all of the compounds of IV and IVc, and the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4), references to any bonded hydrogen atoms may also include deuterium atoms bonded at the same position. Replacing hydrogen atoms with deuterium atoms is common in the art. See, for example, US Pat. Nos. 5,149,820 and 7,317,039, which are hereby incorporated by reference in their entirety. Such deuteration sometimes results in compounds that are functionally indistinguishable from their hydrogenated counterparts, but often results in compounds that have advantageously changed properties relative to non-deuterated forms. For example, in certain instances, replacing a particular bonded hydrogen atom with a deuterium atom slows the catabolism of the deuterated compound relative to a non-deuterated compound so that the deuterated compound is It exhibits a longer half-life in the body of an individual who has been administered such a compound. This is especially true when the catabolism of hydrogenated compounds is mediated by the cytochrome P450 system. See Kushner et al., Can. J. Physiol. Pharmacol. (1999) 77: 79-88, which is hereby incorporated by reference in its entirety.

3. Pharmaceutical Compositions and Formulations In another aspect, the present invention provides compounds of the present invention (eg, formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, as shown herein, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and one of Tables 1A and 1B, 2, 3A and 3B, and 4) and pharmaceutically Further provided is a composition for use as a pharmaceutical or pharmaceutical composition comprising acceptable excipients. In some of such embodiments, the pharmaceutical or pharmaceutical composition is a therapeutically or prophylactically effective amount of a formula I, Ia, Ia1, Ia2, as shown herein, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc compounds and at least one of the compounds of Tables 1A and 1B, 2, 3A, and 3B, and 4 Contains one.

  In some of such embodiments, the composition or pharmaceutical composition is cancer, systemic or chronic inflammation, rheumatoid arthritis, diabetes, obesity, T cell mediated autoimmune disease, false For use in treating blood and other complications associated with these diseases and disorders. In some of such embodiments, the composition or pharmaceutical composition is for use in treating cancer.

  Typically, a compound of the invention (e.g., Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, as shown herein, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, One of the compounds of IVb7, IVb8, and IVc, and the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4), based on total weight, from about 0.01 μg / kg to about 100 mg per day Can be effective in the amount of / kg. The active ingredient can be administered at once, or can be divided into multiple smaller doses to be administered at predetermined time intervals. Suitable dosage units for each administration can be, for example, from about 1 μg to about 2000 mg, preferably from about 5 μg to about 1000 mg. Many pharmacology and toxicology of such other anti-cancer compounds are known in the art. See, for example, Physicians Desk Reference, Medical Economics, Montvale, NJ; and The Merck Index, Merck & Co., Rahway, NJ. Therapeutically effective amounts of such compounds used in the art and suitable unit dosage ranges are the compounds of the present invention (e.g., Formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc compounds, and compounds of Tables 1A and 1B, 2, 3A, and 3B, and 4) may be applicable .

  It should be understood that the above dosage ranges are exemplary only and are not intended to limit the scope of the invention. Individual compounds of the invention (e.g., of formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, as shown herein) IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, The therapeutically effective amount for the compounds of IVb8 and IVc, and the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4) is the activity of the compound used, the patient's body, as will be apparent to those skilled in the art The stability of the compound used in the patient, the severity of the condition to be alleviated, the total body weight of the patient to be treated, the route of administration, the absorption, distribution, and ease of excretion by the body, should be treated With factors including but patient's age and sensitivity are not limited to, it can vary. The amount of administration can be adjusted as various factors change over time.

  In these pharmaceutical compositions, the compounds of the invention (e.g., those of formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, as shown herein, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, Compounds of IVb5, IVb6, IVb7, IVb8, and IVc, and compounds of Tables 1A and 1B, 2, 3A, and 3B, and 4) are in any pharmaceutically acceptable salt form as described above It can be.

  For oral delivery, the compounds of the invention (eg, formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, as shown herein) IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1 , IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5 , IVb6, IVb7, IVb8, and IVc, and the compounds of Tables 1A and 1B, 2, 3A, and 3B, and 4) are pharmaceutically acceptable excipients or carriers (eg, binders, lubricants) Agents, disintegrants, and sweeteners or flavoring agents, all known in the art). The formulation can be delivered orally in the form of a housed gelatin capsule or compressed tablet. Capsules and tablets can be prepared by any convenient technique. Capsules and tablets can also be coated with various coatings known in the art to modify the scent, taste, color and shape of the capsules and tablets. In addition, a liquid carrier (eg, fatty oil) may also be included in the capsule.

  Suitable oral formulations may also be in the form of solutions, suspensions, syrups, chewing gums, wafers, elixirs and the like. If desired, conventional agents for modifying specific forms of aroma, taste, color and shape may also be included.

  Compounds of the invention (e.g., as shown herein, Formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, And IVc compounds, and the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4) are also in the form of solutions or suspensions, or in lyophilized form that can be converted to solutions or suspensions prior to use Can be administered parenterally. In such formulations, diluents or pharmaceutically acceptable carriers such as sterile water and saline buffer can be used. Other conventional solvents, pH buffering agents, stabilizers, antimicrobial agents, surfactants, and antioxidants can all be included. The parenteral formulation can be stored in any conventional container, such as vials and ampoules.

  Routes for topical administration include nasal, buccal, mucosal, rectal, or vaginal application. For topical administration, a compound of the invention (eg, formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, as shown herein) IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1 , IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5 , Compounds of IVb6, IVb7, IVb8, and IVc, and compounds of Tables 1A and 1B, 2, 3A and 3B, and 4) lotions, creams, ointments, gels, powders, pastes, sprays, suspensions, It can be formulated into drops and aerosols. Accordingly, one or more thickeners, wetting agents, and stabilizers can be included in these formulations. A special form for topical administration is delivery via a transdermal patch. Compounds of the present invention (e.g., formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, as shown herein, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, And IVc compounds and methods for preparing transdermal patches that can be used with the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4) are described, for example, in Brown et al., Annual Review of Medicine, 39: 221. -229 (1988), which is incorporated herein by reference.

  Compounds of the present invention (e.g., formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, as shown herein, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, Subcutaneous implantation for sustained release of compounds of IV and IVc, and compounds of Tables 1A and 1B, 2, 3A and 3B, and 4) may also be a suitable route of administration. This may be achieved by the compound of the invention in any suitable formulation (e.g., Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, as shown herein). IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6 , IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3 , IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and one or more of the compounds of Tables 1A and 1B, 2, 3A, and 3B, and 4) under the subcutaneous space (eg, under the anterior abdominal wall) ) With surgical procedures for implantation within. See, for example, Wilson et al., J. Clin. Psych. 45: 242-247 (1984). The hydrogel is a compound of the invention (e.g., of formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, as shown herein) IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3 , IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7 , IVb8, and IVc and the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4) can be used as carriers for sustained release. Hydrogels are generally known in the art. These are typically made by crosslinking high molecular weight biocompatible polymers into a network structure that swells in water to form a gel-like material. Preferably, the hydrogel is biodegradable or bioabsorbable. See, for example, Phillips et al., J. Pharmaceut. Sci., 73: 1718-1720 (1984).

  Compounds of the present invention (e.g., formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, as shown herein, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, And IVc compounds, and the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4) are also bound to water-soluble, non-immunogenic, non-peptide-like, high molecular weight polymers, polymer bound Can form a body. For example, a compound of the invention (e.g., formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, as shown herein, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, One or more of the compounds of IVb8 and IVc, and the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4) are covalently linked to polyethylene glycol to form a conjugate. Typically, such conjugates exhibit improved solubility, stability, and reduced toxicity and immunogenicity. Thus, when administered to a patient, in this conjugate, a compound of the invention (e.g., Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, as shown herein) Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, Compounds of IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and compounds of Tables 1A and 1B, 2, 3A and 3B, and 4) may have a longer half-life in the body , And may show better efficacy. See generally, Burnham, Am. J. Hosp. Pharm., 15: 210-218 (1994). PEGylated proteins are currently used in protein replacement therapy and for other therapeutic applications. For example, PEGylated interferon (PEG-INTRON A®) has been used clinically to treat hepatitis B. PEGylated adenosine deaminase (ADAGEN®) has been used to treat severe combined immunodeficiency disease (SCIDS). PEGylated L-asparaginase (ONCAPSPAR®) has been used to treat acute lymphoblastic leukemia (ALL).

  Polymers and compounds of the invention (e.g., Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, as shown herein) IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, The covalent bond between one or more of the compounds of IVb8 and IVc and the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4) and / or the polymer itself is hydrolyzed under physiological conditions. It is preferable that it can be decomposed | disassembled by. Such conjugates are compounds of the invention (eg, formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, as shown herein. IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1 , IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5 , IVb6, IVb7, IVb8, and IVc, and the compounds of Tables 1A and 1B, 2, 3A, and 3B, and 4) can be readily released in the body. Compounds of the present invention (e.g., formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, as shown herein, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, And the controlled release of compounds of IVc, and the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4) are also commonly known in the art for one or more of the compounds of the present invention. It can be achieved by incorporating into certain microcapsules, nanocapsules, or hydrogels.

  Liposomes can also be represented by compounds of the invention (e.g., formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, as shown herein). IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc compounds, and Tables 1A and 1B, 2, 3A and 3B, and 4 compounds). Liposomes are micelles made from various lipids (eg, cholesterol, phospholipids, fatty acids, and derivatives thereof). Various modified lipids can also be used. Liposomes can reduce the toxicity of the compounds of the present invention and increase their stability. Methods for preparing liposome suspensions containing active ingredients are generally known in the art and can therefore be used with the compounds of the present invention. See, e.g., U.S. Pat. No. 4,522,811; edited by Prescott, Methods in Cell Biology, Vol. XIV, Academic Press, New York, NY (1976).

4. Therapeutic Methods The present invention provides therapeutic methods for treating diseases and injuries that respond to therapy with Nampt inhibitors. As a result, the present invention provides cancer, systemic or chronic inflammation, rheumatoid arthritis, diabetes, obesity, T-cell mediated autoimmune diseases, ischemia, and other complications associated with these diseases and disorders. Therapeutic methods for treating These therapeutic methods involve treating a patient (either a human or another animal) in need of such treatment with a therapeutically effective amount of a compound of the invention (eg, as shown herein, Formula I Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1 IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa , IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Tables 1A and 1B, 2, 3A, and 3B, and 4 Or a pharmaceutical composition containing a therapeutically effective amount of one or more of the compounds of the present invention.

  In addition, the present invention provides compounds of the present invention (eg, formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, as shown herein, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, Pharmaceutical compositions containing compounds of IVb6, IVb7, IVb8, and IVc and compounds of Tables 1A and 1B, 2, 3A and 3B, and 4), or a therapeutically effective amount of a compound of the invention The use of the product for the manufacture of a medicament useful for human treatment.

  In some of such embodiments, the treatment comprises cancer, systemic or chronic inflammation, rheumatoid arthritis, diabetes, obesity, T cell mediated autoimmune disease, ischemia, and these diseases. And therapies for treatment in human patients of other complications associated with the disorder.

  In some of such embodiments, the treatment comprises cancer, systemic or chronic inflammation, rheumatoid arthritis, diabetes, obesity, T cell mediated autoimmune disease, ischemia in a human patient, As well as treatment to delay or reduce the occurrence of other complications associated with these diseases and disorders.

  The present invention also provides for the isolation of isolated cells from a therapeutically effective amount of a compound of the present invention (eg, Formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, as shown herein, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, One or more of the compounds of IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4, or a therapeutically effective amount Treatment with a pharmaceutical composition containing one or more of the compounds of the invention is included.

  As used herein, the phrase “treating ... with a compound” refers to a compound of the invention (eg, formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Of Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Tables 1A and 1B, 2, 3A and 3B, and 4) Or a pharmaceutical composition containing one or more of the compounds of the invention may be administered directly to an isolated cell or animal, or another agent may be administered to the cell or animal. ,Book One or more presentation of formation of the light compounds means any cause in cells or in animals.

  In some embodiments, the invention provides a method of inhibiting the activity of Nampt in human cells, wherein the method comprises treating the cells with a compound of the invention (eg, as shown herein) , Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, Compounds IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Tables 1A and 1B, 2, 3A, and 3B And 4 compounds). In some of such embodiments, the cells are with the body of a human patient.

  Preferably, the methods of the invention are performed on cells in vitro or in warm-blooded animals (especially mammals, and more particularly humans) in an effective amount of a compound of the invention (eg, as shown herein). Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7 IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc , IV, IVa, IVa1, IVa2, IVa3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Tables 1A and 1B, 2, 3A and 3B, and a pharmaceutical comprising another agent that causes the presence or formation of one or more of the compounds of the present invention in a cell or animal Comprising administering a composition.

  As will be appreciated by those skilled in the art, the compounds of the present invention (e.g., Formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, as shown herein) IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb , IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4 , IVb5, IVb6, IVb7, IVb8, and IVc, and one or more of the compounds of Tables 1A and 1B, 2, 3A, and 3B, and 4) can be administered one dose at a time, or It can be divided into multiple smaller doses to be administered at predetermined time intervals. The appropriate dosage unit for each administration can be determined based on the effective daily dose and pharmacokinetics of the compound.

a. Treatment of Cancer In certain embodiments, the present invention provides a method of treating cancer, which comprises a therapeutically effective amount of one or more compounds of the invention (eg, as used herein). Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, as shown IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Tables 1A and 1B, 2 , 3A and 3B, and 4), or one or more compounds of the present invention (eg, formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, as shown herein, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4 IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, And a compound of IVc and a pharmaceutical composition comprising the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4) to a patient.

  In some embodiments, the patient is a human patient.

  In some embodiments, the method includes identifying a patient in need of such treatment. Patients with cancer can be identified by conventional diagnostic techniques known in the art and by the methods discussed herein below.

As noted earlier, Nampt catalyzes the first rate-limiting step in generating NAD ⁺ from NaM, and NAD ⁺ catalyzes cellular ATP, glycolysis, citrate cycle, and oxidative phosphorylation. Is important to produce. Due to these and other mechanisms, reduction of cellular NAD ⁺ levels due to Nampt inhibition results in depletion of cellular ATP, and ultimately cell death. Tumor cells are thought to be more sensitive to loss of NAD ⁺ and ATP than normal cells due to their higher energy requirements and increased dependence on glycolysis. As is known as the “Warburg effect” (Warburg, O. On respiratory impairment in cancer cells. Science 124, 269-270 (1956)), a wide range of cancer cells, regardless of the availability of oxygen, can oxidize phosphorylation. Shows increased glycolysis against oxidation. The shift from oxidative phosphorylation to dependence on glycolysis is due to mitochondrial damage and / or hypoxic tumor microenvironment (Hsu, PP and Sabatini, DM Cancer cell metabolism: Warburg and beyond.Cell 134, 703-707 (2008)). And / or cell reprogramming by oncogenes and / or tumor suppressors (reviewed in Levine, AJ and Puzio-Kuter AMScience. 330, 1340-1344 (2010)) It is done. Nampt inhibitors are similar to inhibitors of other glycolytic enzymes with respect to depleting energy levels in tumor cells, and several of these enzymes are in preclinical or clinical trials for cancer ( Pelicano H. et al., Glycolysis inhibition for anticancer treatment. Oncogene 25,4633-4646 (2006)).

In addition to increased energy requirements, tumor cells are more sensitive to loss of NAD ⁺ due to higher turnover of NAD ⁺ in response to DNA damage and genomic instability. According to this model, as poly (ADP-ribose) polymerase (PARP) produces poly (ADP-ribose) to repair DNA in response to alkylating agents, ionizing radiation, and oxidative stress, NAD Consumes ⁺ (reviewed in Galli M. et al. The nicotinamide phosphoribosyltransferase: a molecular link between metabolism, inflammation, and cancer. Cancer Res. 70, 8-11 (2010)). Indeed, cells can be sensitized to PARP activation by not being able to recruit this NAD ⁺ loss either by reducing Nampt expression or by inhibiting Nampt activity (Rongvaux, Nicotinamide phosphoribosyl transferase / pre-B cell colony-enhancing factor / visfatin is required for lymphocyte development and cellular resistance to genotoxic stress. J. Immunol. 181, 4685-4695 (2008)).

Increased metabolic demand of cancer cells (Luo et al., Cell. 136 (5): 823-37 (2009). Erratum in: Cell., August 21, 2009; 138 (4): 807)) is This suggests that cancer cells require sufficient levels of NAD ⁺ to maintain a cell pool of ATP. This requirement, and the important role played by Nampt in NAD ⁺ synthesis, further suggests that cancer cells have a critical requirement for sufficient Nampt activity. Colon cancer cells (Hufton et al., FEBS Lett. 463 (1-2): 77-82 (1999), Van Beijnum et al., Int. J. Cancer. 101 (2): 118-27 (2002)), ovary (Shackelford et al., Int J. Clin. Exp. Pathol. 3 (5): 522-527 (2010)), prostate cancer (Wang et al., Oncogene 30: 907-921 (2011)) and GBM cancer (Reddy Et al., Cancer Biol. Ther. 7 (5): 663-8 (2008)), and the suggestion of amplification of the gene encoding Nampt in several other cancers is consistent with this assumption. . Immunohistochemical analysis suggests that strong expression of Nampt occurs in more than 20% of breast, lung, malignant lymphoma, ovarian, pancreatic, prostate and testicular cancer biopsies ( www.proteinatlas.org). In addition to the role played by NAD ⁺ as a coenzyme in the redox reaction, NAD ⁺ also has mono-ADP ribosyltransferase and poly-ADP ribosyltransferase (PARP), class III histone deacetylase (sirtuin) and ADP-ribose. Acts as a substrate for cyclase. PARP appears to be a major consumer of cellular NAD ⁺ (Paine et al., Biochem. J. 202 (2): 551-3 (1982)), and evidence suggests that oral cancer (Das, BR, Cancer Lett. 73 (1): 29-34 (1993)), hepatocellular carcinoma (Shiobara et al., J. Gastroenterol. Hepatol. 16 (3): 338-44 (2001), Nomura et al., J Gastroenterol. Hepatol. 15 (5): 529-35 (2000)), rectal cancer (Yalcintepe et al., Braz. J. Med. Biol. Res. 38 (3): 361-5 (2005); Epub March 8, 2005), As well as increased poly ADP-ribosylation activity in leukemia and ovarian cancer (Singh N, Cancer Lett. 58 (1-2): 131-5 (1991)). Increased ADP-ribosylation in cancer is associated with DNA repair (Durkacz et al., Nature. 283 (5747): 593-6 (1980); deMurcia et al., Proc. Natl. Acad. Sci. USA 94 (14): 7303-7. (1997), Simbulan-Rosenthal et al., Proc. Natl. Acad. Sci. USA. 96 (23): 13191-6 (1999)), as well as the need to maintain genomic integrity despite genomic incompleteness It may reflect the role of PARP in sex and consequent point mutations, deletions, chromosomal rearrangements and aneuploidy accumulation (Hartwell and Kastan, Science. 266 (5192): 1821-8 (1994)). PARP-1 itself has been reported to be overexpressed in breast cancer, where its expression is inversely correlated with genomic instability (Biechi et al., Clin. Cancer Res. 2 (7): 1163-7 (1996)).

  Furthermore, Nampt transcription has been used in colon cancer (van Beijnum JR, et al. Target validation for genomics using peptide-specific phage antibodies: a study of five gene products overexpressed in colorectal cancer.Int.J.Cancer.101,118-127 (2002). ; And Hufton SE, et al. A profile of differentially expressed genes in primary colorectal cancer using suppression subtractive hybridization.FEBS Lett. 463, 77-82 (1999)) and glioblastoma cancer (Reddy PS, et al. PBEF1 / NAmPRTase / Visfatin: a potential malignant astrocytoma / glioblastoma serum marker with prognostic value.Cancer Biol.Ther. 7,663-668 (2008)), and the Nampt gene is amplified in other cancers. It is still possible.

  Accordingly, in one embodiment, the invention provides a method of treating a cancer that overexpresses Nampt, wherein the method comprises a therapeutically effective amount of one or more compounds of the invention (eg, as used herein). Formulas I, Ia, Ia1, Ia2, Ia2, Ib1, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5 IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10 IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Tables 1A and 1B, 2, 3A and 3B, and 4 compounds), or one or more compounds of the invention (eg, formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, as shown herein) , Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, A pharmaceutical composition comprising a compound of IVb6, IVb7, IVb8, and IVc and a compound of Tables 1A and 1B, 2, 3A, and 3B, and 4).

  In view of the above, inhibition of Nampt activity is believed to be effective in the treatment of a wide range of cancers. Instructions for this claim are found in the Examples section below. Specifically, the section titled “Nampt inhibitor probes that are cytotoxic to a wide variety of cancer cell types”. As a result, the present invention provides methods for treating a wide range of cancers by administering a therapeutically effective amount of one or more of the compounds of the present invention. Specifically, cancer cell types for colon cancer, prostate cancer, breast cancer, NSCLC, sarcoma, pancreatic cancer, SCLC, gastric cancer, myeloma, ovarian cancer, lymphoma, and glioma cancer Is a compound of the invention (e.g., as shown herein, of formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, Killed by compounds of IVb8, and IVc, and compounds of Tables 1A and 1B, 2, 3A and 3B, and 4).

  Accordingly, in one embodiment, the invention provides a method of treating colon cancer, which method comprises a therapeutically effective amount of one or more compounds of the invention (eg, as set forth herein). Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7 IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc , IV, IVa, IVa1, IVa2, IVa3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Tables 1A and 1B, 2, 3A and 3B and 4), or one or more compounds of the invention (eg, formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, as shown herein) , II, IIa, IIa1, IIa2, IIa3, IIa4 IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, And a compound of IVc and a pharmaceutical composition comprising the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4) to a patient.

  Accordingly, in one embodiment, the invention provides a method of treating prostate cancer, the method comprising a therapeutically effective amount of one or more compounds of the invention (eg, as set forth herein). Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7 IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc , IV, IVa, IVa1, IVa2, IVa3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Tables 1A and 1B, 2, 3A and 3B and 4), or one or more compounds of the invention (eg, formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, as shown herein) II, IIa, IIa1, IIa2, IIa3, IIa 4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, And a pharmaceutical composition comprising the compounds of IVb8 and IVc and the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4).

  Accordingly, in one embodiment, the invention provides a method of treating breast cancer, wherein the method comprises a therapeutically effective amount of one or more compounds of the invention (eg, as set forth herein, Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV , IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Tables 1A and 1B, 2, 3A, and 3B, And one or more compounds of the present invention (eg, formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, as shown herein) IIa, IIa1, IIa2, IIa3, IIa4, II b, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, And a compound of IVc and a pharmaceutical composition comprising the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4) to a patient.

  Accordingly, in one embodiment, the present invention provides a method of treating non-small cell lung cancer (NSCLC), which comprises a therapeutically effective amount of one or more compounds of the present invention (eg, herein Formulas I, Ia, Ia1, Ia2, Ia2, Ib1, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5 IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10 IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Tables 1A and 1B, 2, 3A and 3B, and 4 compounds), or one or more compounds of the invention (eg, formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, as shown herein) , Ic, Id, II, IIa, IIa1, IIa2 IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2 , IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6 , IVb7, IVb8, and IVc and a pharmaceutical composition containing the compounds of Tables 1A and 1B, 2, 3A, and 3B, and 4).

  Accordingly, in one embodiment, the invention provides a method of treating sarcoma cancer, wherein the method comprises a therapeutically effective amount of one or more compounds of the invention (eg, as set forth herein). Such as Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc compounds, and Tables 1A and 1B, 2, 3A And compounds of 3B and 4), or one or more compounds of the invention (eg, formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, as shown herein) Id, II, IIa, IIa1, IIa2, IIa3, IIa 4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, And a pharmaceutical composition comprising the compounds of IVb8 and IVc and the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4).

  Accordingly, in one embodiment, the invention provides a method of treating pancreatic cancer, the method comprising a therapeutically effective amount of one or more compounds of the invention (eg, as set forth herein). Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7 IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc , IV, IVa, IVa1, IVa2, IVa3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Tables 1A and 1B, 2, 3A and 3B and 4), or one or more compounds of the invention (eg, formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, as shown herein) , II, IIa, IIa1, IIa2, IIa3, IIa4 IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, And a compound of IVc and a pharmaceutical composition comprising the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4) to a patient.

  Accordingly, in one embodiment, the invention provides a method of treating SCLC cancer, which method comprises a therapeutically effective amount of one or more compounds of the invention (eg, as set forth herein). Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7 IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc , IV, IVa, IVa1, IVa2, IVa3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Tables 1A and 1B, 2, 3A and 3B and 4), or one or more compounds of the invention (eg, formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, as set forth herein) II, IIa, IIa1, IIa2, IIa3, IIa4, I Ib, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, And a compound of IVc and a pharmaceutical composition comprising the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4) to a patient.

  Accordingly, in one embodiment, the invention provides a method of treating gastric cancer, wherein the method comprises a therapeutically effective amount of one or more compounds of the invention (eg, as set forth herein, Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV , IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Tables 1A and 1B, 2, 3A, and 3B, And one or more compounds of the present invention (eg, formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, as shown herein) IIa, IIa1, IIa2, IIa3, IIa4, II b, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, And a compound of IVc and a pharmaceutical composition comprising the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4) to a patient.

  Accordingly, in one embodiment, the present invention provides a method of treating myeloma cancer, the method comprising a therapeutically effective amount of one or more compounds of the present invention (eg, as shown herein). Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6 IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11 , IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Tables 1A and 1B, 2, 3A and 3B, and 4), or one or more compounds of the invention (eg, formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, as shown herein) , Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, And a pharmaceutical composition comprising the compounds of IVb8 and IVc and the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4).

  Accordingly, in one embodiment, the present invention provides a method of treating ovarian cancer, the method comprising a therapeutically effective amount of one or more compounds of the present invention (eg, as set forth herein). Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7 IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc , IV, IVa, IVa1, IVa2, IVa3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Tables 1A and 1B, 2, 3A and 3B and 4), or one or more compounds of the invention (eg, formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, as shown herein) , II, IIa, IIa1, IIa2, IIa3, IIa4 IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, And a compound of IVc and a pharmaceutical composition comprising the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4) to a patient.

  Accordingly, in one embodiment, the invention provides a method of treating lymphoma cancer, which method comprises a therapeutically effective amount of one or more compounds of the invention (eg, as set forth herein). Such as Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc compounds, and Tables 1A and 1B, 2, 3A And compounds of 3B and 4), or one or more compounds of the invention (eg, formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, as shown herein) Id, II, IIa, IIa1, IIa2, IIa3 IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3 , IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7 , IVb8, and IVc, and Tables 1A and 1B, 2, 3A, and 3B, and 4).

  Accordingly, in one embodiment, the present invention provides a method of treating glioma cancer, wherein the method comprises a therapeutically effective amount of one or more compounds of the present invention (eg, as used herein). Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, as shown IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Tables 1A and 1B, 2 , 3A and 3B, and 4), or one or more compounds of the present invention (eg, formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, as shown herein, Ic, Id, II, IIa, IIa1, IIa2, IIa3 IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3 , IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7 , IVb8, and IVc, and Tables 1A and 1B, 2, 3A, and 3B, and 4).

  As used herein, the term “cancer” has the meaning customary in the art. Cancer includes any condition of the animal or human body that is characterized by abnormal cell growth. Cancers to be treated include a group of diseases characterized by the uncontrolled growth and spread of abnormal cells. The compounds of the present invention have been shown to be effective in a variety of standard cancer models and are therefore believed to have utility in the treatment of a wide range of cancers. However, preferred methods of the invention include treating cancers that have been found to respond predominantly to treatment with Nampt inhibitors. Further, “treating cancer” refers to treating a patient at any one of several stages of cancer, including those that are diagnosed but still asymptomatic. Should be understood to encompass.

  A specific cancer that can be treated by the method of the invention is a cancer that responds predominantly to treatment with a Nampt inhibitor. Such cancers include Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, mantle cell leukemia, multiple myeloma, neuroblastoma, breast carcinoma, ovarian carcinoma, Lung carcinoma, Wilms tumor, cervical carcinoma, testicular carcinoma, soft tissue sarcoma, primary macroglobulinemia, bladder carcinoma, chronic granulocytic leukemia, primary brain carcinoma, malignant melanoma, small cell lung carcinoma, gastric carcinoma, colon Carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, head or neck carcinoma, osteogenic sarcoma, pancreatic carcinoma, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, striated Sarcoma, capage sarcoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial carcinoma, polycythemia vera, book Sexually thrombocytosis, adrenal cortex carcinoma, skin cancer, and prostatic carcinomas include, but are not limited to.

a.1 Methods for identifying cancers most likely to be treated with Nampt inhibitors Importantly, NAD ⁺ can also be generated by several Nampt-independent pathways. These pathways include: (1) de novo synthesis from L-tryptophan via the kynuclenin pathway; (2) from nicotinic acid (NA) via the Preiss-Handler pathway; and (3) from nicotinamide riboside or nicotinic acid riboside. Nicotinamide / nicotinic acid riboside kinase is mentioned (Khan, JA et al., Nicotinamide adenine dinucleotide metabolism as an attractive target for drug discovery.Expert Opin.Ther.Targets.11 (5): 695-705 (2007) Is outlined in). However, these different pathways of NAD ⁺ synthesis are generally tissue specific. This de novo pathway is present in the liver, brain, and immune cells, the Priess-Handler pathway is primarily active in the liver, kidney, and heart, and the nicotinamide riboside kinase pathway Nrk2 is found in the brain, heart, And expressed in skeletal muscle (Bogan, KL and Brenner, C. Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD ⁺ precursor vitamins in human nutrition. Annu. Rev. Nutr. 28: 115-30 (2008 ) And Tempel, W. et al., Nicotinamide riboside kinase structures reveal new pathways to NAD ⁺ .PLoS Biol. 5 (10): e263 (2007)).

Of these alternative pathways of NAD ⁺ synthesis, the Preiss-Handler pathway is probably the most important for cancer cells. The first rate-limiting step in this pathway, the conversion of nicotinic acid (NA) to nicotinic acid mononucleotide (NAMN), is catalyzed by the enzyme Naprt1.

While not wishing to be bound by theory, one way to satisfy the patient and potentially extend the therapeutic window of the compounds of the present invention is that the level of Naprt1 expression is reduced or present The conclusion is that cancer is not identified. Such cancers are theoretically difficult to replace cellular NAD ⁺ through this alternative route, while being treated with Nampt inhibitors. Thus, these cancers should be more sensitive to treatment with the compounds of the present invention.

  Thus, embodiments of the present invention include compounds of the present invention (eg, formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, as shown herein) IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb , IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4 , IVb5, IVb6, IVb7, IVb8, and IVc, and the compounds of Tables 1A and 1B, 2, 3A, and 3B, and 4). This method is used to obtain a biopsy sample of this cancer, and to reduce the expression level of the enzyme in the pathway for NAD biosynthesis (e.g., tryptophan, quinuclein pathway, nicotinic acid salvage pathway, nicotinamide riboside pathway). Including the step of determining against sex control tissue, where the expression level of enzymes (eg Naprt1, Qprt, NRK-1) in such pathways is reduced relative to non-cancerous control tissue This cancer is identified as likely to be treatable with the compounds of the present invention.

  In some of such embodiments, the method of determining the expression level of a Naprt1 gene comprises determining the level of expression of a transcript encoding Naprt1 (ie, mRNA encoding Naprt1), or Naprt1 protein Including determining the level of expression of itself. For these embodiments, any acceptable means of determining the expression level of either the transcript encoding Naprt1 or the Naprt1 protein itself can be utilized, and such acceptable means are sufficiently eukaryotic. Within the level of skill of those skilled in the art who are skilled in determining the level of cellular gene expression. Such acceptable means can include, for example, quantitative PCR (qPCR) to measure the level of transcripts encoding Naprt1, or an ELISA to measure the level of expressed Naprt1 protein. . The specific methods involved in determining the expression of a particular eukaryotic gene are well known in the art.

  Furthermore, embodiments of the invention encompass methods of treating cancer, wherein the cancer cells exhibit low levels of Naprt1 expression. Accordingly, in one embodiment, the present invention provides a method of treating a cancer that exhibits low levels of Naprt1 expression, wherein the method comprises a therapeutically effective amount of one or more compounds of the present invention (eg, Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, as shown in the document IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9 , IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Tables 1A and 1B, 2, 3A and 3B, and 4), or one or more compounds of the invention (eg, formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, as shown herein) , Ib3, Ic, Id, II, IIa IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb , IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4 , IVb5, IVb6, IVb7, IVb8, and IVc, and the pharmaceutical compositions containing the compounds of Tables 1A and 1B, 2, 3A, and 3B, and 4).

  Cell lines were treated with exemplary compounds of the invention and screened for NA rescue and Naprt1 expression by immunoblotting and quantitative RT-PCR (see NA Rescue and Naprt1 expression assay section below). . Naprt1 expression was minimal in brain cancer, lung cancer, lymphoma, myeloma and osteosarcoma. Furthermore, glioblastoma cell lines and sarcoma cell lines that have been reported to be resistant to NA rescue have been found to have reduced Naprt1 expression (Watson, et al. Mol. Cell Biol. 29 (21): 5872-88 (2009)).

  Accordingly, in one embodiment, the invention provides a method of treating brain cancer, such as glioblastoma, which comprises a therapeutically effective amount of one or more compounds of the invention (eg, Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, as shown in the document IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9 , IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Tables 1A and 1B, 2, 3A and 3B, and 4), or one or more compounds of the invention (eg, formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, as shown herein) , Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, And a pharmaceutical composition comprising a compound of IVb5, IVb6, IVb7, IVb8, and IVc, and a compound of Tables 1A and 1B, 2, 3A, and 3B, and 4).

  Accordingly, in one embodiment, the invention provides a method of treating lung cancer, wherein the method comprises a therapeutically effective amount of one or more compounds of the invention (eg, as set forth herein, Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV , IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Tables 1A and 1B, 2, 3A, and 3B, And one or more compounds of the present invention (eg, formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, as shown herein) IIa, IIa1, IIa2, IIa3, IIa4, II b, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, And a compound of IVc and a pharmaceutical composition comprising the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4) to a patient.

  Accordingly, in one embodiment, the invention provides a method of treating osteosarcoma cancer, wherein the method comprises a therapeutically effective amount of one or more compounds of the invention (eg, as shown herein). Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6 IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11 , IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Tables 1A and 1B, 2, 3A and 3B, and 4), or one or more compounds of the invention (eg, formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic as shown herein) , Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, And a pharmaceutical composition comprising the compounds of IVb8 and IVc and the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4).

a.2 Method of limiting the toxicity of the compounds of the present invention by administering NA In view of the NA rescue phenomenon, cancers with reduced or absent levels of Naprt1 expression may be treated with the Nampt inhibitor of the present invention. Should be more sensitive to treatment, administration of NA to patients with such cancers may prevent toxicity in other tissues associated with Nampt inhibition.

To support this concept, an experiment was conducted to show that mice given NA survived with a dose of Nampt inhibitor that exceeded the maximum tolerated dose (Beauparlant P. et al. Preclinical development of the nicotinamide phosphoribosyl transferase inhibitor prodrug GMX1777.Anticancer Drugs. 20 (5): 346-54 (2009) and Watson, et al. The small molecule GMX1778 is a potent inhibitor of NAD ⁺ biosynthesis: strategy for enhanced therapy in nicotinic acid phosphoribosyltransferase 1-deficient tumors.Mol See also Cell Biol. 29 (21): 5872-88 (2009)). This phenomenon is referred to in the art as “NA rescue”.

  Cell lines were treated with exemplary compounds of the invention and screened by immunoblotting and quantitative RT-PCR for NA rescue and Naprt1 expression. The lack of NA rescue was greatest in brain cancer, lung cancer, lymphoma, myeloma, and osteosarcoma. Furthermore, glioblastoma cell lines and sarcoma cell lines that have been reported to be resistant to NA rescue were found to have reduced Naprt1 expression (Watson, et al. Mol. Cell. Biol. 29 (21): 5872-88 (2009)).

  Accordingly, in some embodiments, the methods of treating cancer disclosed herein include treating nicotinic acid, or a compound capable of forming nicotinic acid in vivo, with a compound of the invention (eg, Formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, as shown herein IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8 , IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Table Further administration in addition to administration of 1A and 1B, 2, 3A and 3B, and 4 compounds). In some of such embodiments, the compounds of the invention can be administered at a dose that exceeds the maximum tolerated dose for a particular compound of the invention as determined for monotherapy.

  In some of such embodiments, the administration of NA comprises administering NA prior to administering one or more of the compounds of the invention, one or more of NA and the compounds of the invention. Or the patient is first treated with one or more of the compounds of the invention followed by subsequent administration of NA.

b. Treatment of systemic or chronic inflammation Nampt expression in visceral adipose tissue has been found to correlate with the expression of pro-inflammatory genes CD68 and TNFα (Chang et al .; Metabolism. 59 (1) : 93-9 (2010)). Several studies have focused on increasing reactive oxygen species and activation of NF-kappaB in response to Nampt expression (Oita et al .; Pflugers Arch. (2009); Romacho et al .; Diabetologia. 52 (11): 2455- 63 (2009)). Nampt serum levels have been found to increase in patients with inflammatory bowel disease and correlate with disease activity (Moschen et al; Mutat. Res. (2009)). One study still suggests a specific mechanism for Nampt in inflammation. That is, high levels of Nampt increase cellular NAD ⁺ levels, resulting in post-transcriptional up-regulation of TNF via SirT6, a NAD-dependent deacetylase (Van Gool et al. Nat. Med. 15 (2): 206-10 (2009)). Furthermore, inhibition of Nampt reduced the levels of IL-6 and TNF-α, inflammatory cytokines (Busso et al. PLoS One.21; 3 (5): e2267 (2008)). In another study, Nampt inhibition was found to prevent TNF-α and IFN-γ production in T-lymphocytes (Bruzzone et al; PLoS One .; 4 (11): e7897 (2009)) .

  In view of the above, inhibition of Nampt activity is believed to be effective in the treatment of systemic or chronic inflammation resulting from a wide variety of causes. Consequently, the present invention provides a method of treating systemic or chronic inflammation by administering a therapeutically effective amount of one or more of the compounds of the present invention.

c. Treatment of rheumatoid arthritis
Nampt levels are increased in a mouse model of arthritis, and treatment of these mice with Nampt inhibitors reduced the symptoms of arthritis (Busso et al. PLoS One.21; 3 (5): e2267 (2008)) . Nampt inhibition can also reduce the activity of poly (ADP ribose) polymerase (PARP) by relying on NAD as a substrate for PARP, so that Nampt inhibitors can be used either alone or in combination with PARP inhibitors. However, it can be effective in any disease treatable with a PARP inhibitor. In this regard, PARP inhibitors have shown efficacy in models of arthritis (Kroger et al. Inflammation. 20 (2): 203-215 (1996)).

  In view of the above, inhibition of Nampt activity is believed to be effective in the treatment of RA. Consequently, the present invention provides a method of treating RA by administering a therapeutically effective amount of one or more of the compounds of the present invention either alone or in combination with a PARP inhibitor. .

d. Treatment of obesity and diabetes
Nampt (also known as visfatin) has been described as an adipokine found in visceral fat that acts as an insulin mimetic (Fukuhara et al. Science 307: 426-30 (2007)). The paper was finally withdrawn, and other groups failed to confirm that Nampt binds to the insulin receptor. Nevertheless, many subsequent papers continue to report a correlation between Nampt expression and obesity and / or diabetes. In one paper, increased Nampt expression and circulating Nampt levels were found in obese patients (Catalan et al; Nutr. Metab. Cardiovasc. Dis. (2010)), but different studies show that this correlation is 2 It was found to be specific only to obese patients with type 2 diabetes (Laudes et al; Horm. Metab. Res. (2010)). Yet another study reported a correlation between BMI, body fat mass, and Nampt plasma levels, but inversely correlated with Nampt's cerebrospinal fluid levels (Hallschmid et al; Diabetes. 58 (3): 637-40 (2009)). Patients who had significant weight loss after bariatric surgery showed reduced levels of Nampt mRNA in the liver (Moschen et al .; J. Hepatol. 51 (4): 765-77 (2009)). Finally, a rare single nucleotide polymorphism was identified in Nampt, which correlated with severe obesity (Blakemore, et al; Obesity 17 (8): 1549-53 (2009)). In contrast to these reports, Nampt levels were not altered in a rat model of obesity (Mercader et al; Horm. Metab. Res. 40 (7): 467-72 (2008)). Furthermore, circulating levels of Nampt correlated with HDL-cholesterol and inversely with triglycerides (Wang et al .; Pflugers Arch. 454 (6): 971-6 2007)). This is a debate against Nampt's involvement in obesity. Finally, Nampt has been shown to be a positive regulator of insulin secretion by β-cells (Revollo et al. Cell Metab. 6 (5): 363-75 (2007)). This effect appears to require Nampt's enzymatic activity and can be mimicked in cell culture models by exogenous addition of NaMN.

  Nampt inhibition can reduce the activity of poly (ADP ribose) polymerase (PARP) by relying on NAD as a substrate for PARP, so Nampt inhibitors can be used either alone or in combination with PARP inhibitors. May be effective in any disease treatable with a PARP inhibitor. In this regard, PARP inhibitors have shown efficacy in models of type I diabetes (Drel et al. Endocrinology. December 2009; 150 (12): 5273-83. Epub October 23, 2009).

  In view of the above, despite the contrasting results described, inhibition of Nampt activity is associated with obesity and diabetes, as well as other complications associated with these, and other metabolic diseases and disorders. It is considered effective in the treatment. As a result, the present invention provides obesity and diabetes, as well as other complications associated therewith, as well as other metabolic diseases and by administering a therapeutically effective amount of one or more of the compounds of the present invention. A method of treating a disorder is provided.

Treatment of eT cell-mediated autoimmune diseases
Nampt expression has been shown to be up-regulated in activated T cells (Rongavaux et al .; J. Immunol. 181 (7): 4685-95 2008)), and phase I clinical trials have demonstrated Nampt inhibitors Report lymphopenia in patients treated with von Heideman et al. (Reviewed in Cancer Chemother. Pharmacol. (2009)). In addition, in experimental autoimmune encephalomyelitis (EAE), a mouse model of T cell autoimmune disease, Nampt inhibition reduced clinical disease scores and spinal cord demyelination (Bruzzone et al; PLoS One.4 (11 ): e7897 (2009)).

  In view of the above, inhibition of Nampt activity is believed to be effective in the treatment of T cell mediated autoimmune diseases and other complications associated with the diseases and disorders. As a result, the present invention treats T cell mediated autoimmune diseases and other complications associated with these diseases and disorders by administering a therapeutically effective amount of one or more of the compounds of the present invention. Provide a way to do it.

f. Treatment of ischemia
Nampt inhibition can reduce the activity of poly (ADP ribose) polymerase (PARP) by relying on NAD as a substrate for PARP, so Nampt inhibitors can be used either alone or in combination with PARP inhibitors. May be effective in any disease treatable with a PARP inhibitor. FR247304, a PARP inhibitor, has been shown to attenuate neuronal damage in in vitro and in vivo models of cerebral ischemia (Iwashita, et al. J. Pharmacol Exp. Ther. 310 (2): 425-36 ( 2004) .Epub April 9, 2004). Similarly, neurodegenerative diseases in which PARP inhibitors are induced by chronic hypoperfusion (including ocular ischemia syndrome) (Mester et al. Neurotox. Res. 16 (1): 68-76 (2009) Epub 2009 (9 April) or ischemic reperfusion (Crawford et al. Surgery. 2 February 2010 [Epub ahead of print]) has been suggested to be effective.

  In view of the above, inhibition of Nampt activity is believed to be effective in the treatment of ischemia and other complications associated with this condition. Consequently, the present invention relates to ischemia and this condition by administering a therapeutically effective amount of one or more of the compounds of the present invention either alone or in combination with a PARP inhibitor. Provide a method of treating other complications.

5. Combination Therapy In a further aspect, the present invention also addresses cancer, systemic or chronic inflammation, rheumatoid arthritis, diabetes, obesity, T cell mediated autoimmune diseases, ischemia, and these diseases and disorders. Providing a method for combination therapy to treat other related complications, which can be used to treat patients in need of cancer, systemic or chronic inflammation, rheumatoid arthritis, diabetes, obesity Together with therapeutically effective amounts of one or more other compounds that have been shown to be effective in the treatment of T cell mediated autoimmune diseases, ischemia, and other complications associated with these diseases and disorders By treatment with a therapeutically effective amount of one of the compounds of the present invention.

  In some embodiments, the present invention provides a patient (human or another animal's) in need of treatment with one of the compounds of the present invention in combination with one or more other anti-cancer therapies. By treating any), a method for combination therapy for treating cancer is provided. Such other anti-cancer treatments include traditional chemotherapeutic agents, targeting agents, radiation therapy, surgery, hormone therapy, immune adjuvants, and the like. In combination therapy, one of the compounds of the invention (eg, formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, as shown herein) IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb , IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4 , IVb5, IVb6, IVb7, IVb8, and IVc, and the compounds of Tables 1A and 1B, 2, 3A, and 3B, and 4) can be administered separately from one or more other anti-cancer treatments? Or can be administered together.

Specifically, Nampt inhibition has been shown to sensitize cells to the effects of various chemotherapeutic or cytotoxic agents. Specifically, Nampt inhibition inhibits cells against amiloride, mitomycin C, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), melphalan, daunorubicin, cytarabine (Ara-C), and etoposide. (Ekelund, S. et al. Chemotherapy 48: 196-204 (2002); Rongvaux, A. et al. The Journal of Immunology 181 (7): 4685-95 (2008); Martinsson , P. et al. British Journal of Pharmacology 137: 568-73 (2002); Pogrebniak, A. et al. European Journal of Medical Research 11 (8): 313-21 (2006)). Lactate dehydrogenase A inhibitor, prostaglandin H2 synthase 2 (PGHS-2) inhibitor, together with Nampt inhibitor, is also considered to be an effective cancer treatment. Although the mechanism behind this synergy between Nampt inhibitors and other cell killing agents has not been fully investigated, Nampt inhibition is at doses and exposure times that are not clearly toxic to cells. , Leading to a decrease in cellular levels of NAD ⁺ . While not wishing to be bound by theory, sublethal NAD ⁺ reduction activates cells and other cytotoxic agents, especially the DNA repair enzyme poly (ADP-ribose) polymerase (PARP) It is thought that it is easy to be attacked by the compound to be made. This is because PARP requires NAD ⁺ as a substrate and consumes NAD ⁺ during its enzymatic action (FIG. 1A).

  Accordingly, in some embodiments, the present invention provides methods for treating the cancers disclosed herein, wherein a therapeutically effective amount of a PARP activator is administered to a compound of the invention (eg, Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, as shown in the document IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9 IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc) and Table 1A and In addition to administering the compounds of 1B, 2, 3A and 3B, and 4, it further includes administering to the patient.

  Further, in some such embodiments, the cancer cells have a functional homologous recombination (HR) system. In some of such embodiments, the methods further include the step of confirming that the cancer cells have a functional HR system. Methods for performing such confirmation are known in the art. Further, in addition to the PARP activator, in some embodiments, the methods of treating cancer disclosed herein further comprise administering to the patient a therapeutically effective amount of a non-DNA damaging agent. However, this non-DNA damaging agent is not a PARP activator and is not a compound of the present invention. For example, if the cancer has a functional HR system to repair DNA damage, additional chemotherapy can be administered that is independent of DNA damage for efficacy. Chemotherapy that does not damage DNA is known in the art.

  Agents or treatments that may be able to activate the PARP enzyme include alkylating agents (methyl methanesulfonate (MMS), N-methyl-N′nitro-N-nitrosoguanidine (MNNG), nitrosourea (N- Methyl-N-nitrosourea (MNU), streptozotocin, carmustine, lomustine), nitrogen mustard (melphalan, cyclophosphamide, uramustine, ifosfamide, chlorambucil, mechlorethamine), alkylsulfonate (busulfan), platin (cisplatin) , Oxaliplatin, carboplatin, nedaplatin, satraplatin, triplatin tetranitrate), non-classical DNA alkylating agents (temozolomide, dacarbazine, mitozolamide, procarbazine, altretamine)), radiation (X Rays, gamma rays, charged particles, UV, systemic or targeted radioisotope therapy), and other DNA damaging agents (eg, topoisomerase inhibitors (camptothecin, beta-lapachone, irinotecan, etoposide), anthracyclines (Doxorubicin, daunorubicin, epirubicin, idarubicin, valrubicin, mitozantrone), reactive oxygen generators (menadione, peroxynitrite), and antimetabolites (5-FU, raltetrexed, pemetrexed, plala Pralatrexate, methotrexate, gemcitabine, thioguanine, fludarabine, azathioprine, cytosine arabinoside, mercaptopurine, pentostatin, cladribine, folic acid, floxuridine)) But it is not limited to these.

  It is further contemplated that tumors or tumor cell lines treated with compounds that directly or indirectly inhibit the enzyme thymidylate synthase (TS) may also be more sensitive to Nampt inhibitors (eg, compounds of the invention).

  Accordingly, in some embodiments, the present invention provides methods of treating the cancers disclosed herein, which methods further comprise a therapeutically effective amount of a thymidylate synthase inhibitor. (E.g., Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, as shown herein, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc And administration of the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4) to a patient.

  In some embodiments, the thymidylate synthase inhibitor directly or indirectly inhibits thymidylate synthase. Thymidylate synthase inhibitors include 5-FU, raltitrexed, pemetrexed, and other TS inhibitors developed over the past decades.

  It is also contemplated that agents that promote abnormal uracil uptake into DNA can also make subjects administered such agents more sensitive to Nampt inhibitors (eg, compounds of the invention). Any inhibitor of thymidylate synthase (TS) causes uracil incorporation into DNA. Other agents, such as inhibitors of dihydrofolate reductase (eg, methotrexate), have also been shown to cause abnormal uptake of uracil into DNA.

  Accordingly, in some embodiments, the present invention provides methods of treating the cancers disclosed herein, which methods further comprise a therapeutically effective amount that promotes abnormal uracil uptake into DNA. The agent may be a compound of the invention (eg, formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, as shown herein) IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3 , IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7 , IVb8, and IVc, and Tables 1A and 1B, 2, 3A and 3B, and 4)).

  In view of the above, some embodiments of the present invention include the use of a compound of the present invention and a second chemotherapeutic agent, wherein the second chemotherapeutic agent is a compound of the present invention. Have been found to work synergistically with one or more of them, such as compounds or treatments that activate PARP, compounds or treatments that induce DNA damage, compounds or treatments that inhibit TS, and / or A compound or treatment that promotes abnormal uracil uptake into DNA, a compound or treatment that inhibits the proteasome or a specific kinase.

  In certain embodiments of this aspect of the invention, the second chemotherapeutic agent is at least methyl methanesulfonate (MMS), mechloretamine, streptozotocin, 5-fluorouracil (5-FU), raltitrexed, methotrexate, bortezomib ( bortezomib), PI-103, and dasatinib.

In HCT116 cells, olaparib, a potent and selective PARP inhibitor, does not synergize with Nampt inhibitor and in fact antagonism is observed, where olaparib removes cells from death induced by Nampt inhibitor. Some protection. PARP inhibitors are relatively benign on cells that have a functional homologous recombination (HR) system to repair double-stranded DNA damage (such as HCT116 cells) (Ashworth A. Journal of Clinical Oncology 26 (22 ): 3785-90 (2008)). Indeed, the model (FIG. 1A) predicts that inhibition of enzymes that consume NAD ⁺ (eg, PARP) protects HR active cells from Nampt inhibition. However, in cells that have lost BRCA tumor suppressor function, HR function is impaired and these cells are killed by PARP inhibitors (Ashworth A. (2008) Journal of Clinical Oncology 26 (22): 3785- 90). Thus, it was hypothesized that PARP inhibitors that are antagonistic to Nampt inhibitors in most cells synergize with BRCA mutations that render cells HR deficient in cells (FIG. 1B). Indeed, in MDA-MB-436 cells (losing BRCA1 function), Nampt inhibitors (including compounds of the present invention) and the PARP inhibitor olaparib synergized to cause cell death. This result shows that a drug combination of one of the compounds of the present invention with a PARP inhibitor is antagonistic in normal cells (FIG. 1A), but does not have a functional HR system (eg, BRCA tumor suppressor function). It is particularly encouraging, as it suggests synergistic action in cells that have lost (Fig. 1B).

  Other pathways of HR deficiency in oncogenes (other than BRCA sequence mutations) can also lead to sensitivity to combination therapy with PARP inhibition and Nampt inhibitors. These additional mutations (resulting in a “BRCAness” phenotype) include methylation of the BRCA1 promoter and upregulation of BRCA inhibitors (eg, protein EMSY), as documented in ovarian cancer. (Bast R.C. and Mills G.B. Journal of Clinical Oncology 28 (22): 3545-8 (2010)). Further studies show that mutations in the tumor suppressor genes phosphatase and tensin homolog (PTEN), a gene that is frequently mutated in various cancers, reduce HR function and sensitize cells to PARP inhibitors (Mendes-Pereira AM et al. EMBO Molecular Medicine 1: 315-322 (2009)). What provides further evidence for a BRCAness model of PARP inhibitor sensitivity in cell biology studies using RNA interference is 12 distinct functionally important for cells HR sensitized to PARP inhibitors Any mutation of the gene (McCabe et al. Cancer Research 66 (16): 8109-15 (2006)). Finally, recent papers have shown that cells in hypoxia (eg, cells found in the center of virtually all solid tumors) are selectively killed by PARP inhibitors (Chan et al. Cancer) Research 70 (2): 8045-54 (2010)).

  Accordingly, in some embodiments, the present invention provides a method of treating a cancer disclosed herein, which method further comprises treating a therapeutically effective amount of a PARP inhibitor with a compound of the invention (eg, As shown herein, Formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and In addition to administering the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4).

  In some of such embodiments, the cancer cells do not have a functional homologous recombination (HR) system. In some of such embodiments, the method of treating cancer further comprises confirming that the cancer cells have no functional HR system. Methods for performing such confirmation are known in the art.

  In some of such embodiments, the PARP inhibitor is olaparib, AG014699 / PF-01367338, INO-1001, ABT-888, Iniparib, BSI-410, CEP-9722, MK4827, or E7016 is there.

  In some of such embodiments, the methods further comprise administering to the patient a therapeutically effective amount of a DNA damaging agent, wherein the DNA damaging agent is other than a PARP inhibitor. DNA damaging agents are known in the art, and topoisomerase inhibitors (camptothecin, β-lapachone, irinotecan, etoposide), anthracyclines (doxorubicin, daunorubicin, epirubicin, idarubicin, valrubicin, mitozantrone), reactive oxygen generators (menadione, Peroxynitrite) and antimetabolites (5-FU, raltitrexed, pemetrexed, pralatrexate, methotrexate, gemcitabine, thioguanine, fludarabine, azathioprine, cytosine arabinoside, mercaptopurine, pentostatin, cladribine, folic acid, floxuridine ).

  The study was extended to investigate a synergistic combination of Nampt inhibitors and medical standards in specific cancer types. The cancer cell lines used in these studies represented cancer types that were found to be sensitive to Nampt inhibition [eg, non-Hodgkin lymphoma, multiple myeloma, glioma, non- Small cell lung carcinoma (NSCLC), small cell lung carcinoma (SCLC), ovarian cancer and colorectal cancer]. The medical standards in these cancer types tested in the synergistic experiments were 4-HC (form before cyclophosphamide activation), doxorubicin, vincristine, prednisolone, dexamethasone, melphalan, thalidomide, bortezomib, temozolomide Cisplatin, paclitaxel, gefitinib, 5-FU, oxaliplatin, irinotecan, and etoposide. Synergistic cytotoxicity is observed when the compounds of the invention are combined with 4HC in small cell lung cancer (SCLC) and glioma, when combined with temozolomide in glioma, and in colon cancer. It was seen when combined with FU.

  Another specific example of an active agent to which a compound of the invention can be co-administered is L-1-methyltryptophan (L-1MT), an immune adjuvant. In a co-administration study of L-1MT and another inhibitor of Nampt (ie, APO866 [also known as FK866 or WK175]), this combination was found to increase tumor growth in mouse gastric and bladder tumors in immune-competing mice. Has been shown to provide an additional inhibitory effect (Yang et al. Exp. Biol. Med. 235: 869-76 (2010)).

  Accordingly, in one embodiment, the present invention provides a method of treating cancer, wherein the method provides a patient with a therapeutically effective amount of one or more compounds of the present invention (eg, as shown herein). Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6 IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11 , IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Tables 1A and 1B, 2, 3A and 3B, and 4), or one or more compounds of the invention (eg, formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, as shown herein) , Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, Administering a pharmaceutical composition containing the compounds of IVb8 and IVc and the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4), and administering a therapeutically effective amount of temozolomide.

  Accordingly, in one embodiment, the present invention provides a method of treating cancer, wherein the method provides a patient with a therapeutically effective amount of one or more compounds of the present invention (eg, as shown herein). Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6 IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11 , IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Tables 1A and 1B, 2, 3A and 3B, and 4), or one or more compounds of the invention (eg, formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, as shown herein) , Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, Administering a pharmaceutical composition containing the compounds of IVb8 and IVc and the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4) and administering a therapeutically effective amount of 4HC.

  Accordingly, in one embodiment, the present invention provides a method of treating cancer, wherein the method provides a patient with a therapeutically effective amount of one or more compounds of the present invention (eg, as shown herein). Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6 IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11 , IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Tables 1A and 1B, 2, 3A and 3B, and 4), or one or more compounds of the invention (eg, formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, as shown herein) , Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, Including administering a pharmaceutical composition comprising a compound of IVb8 and IVc and a compound of Tables 1A and 1B, 2, 3A and 3B, and 4) and administering a therapeutically effective amount of 5-FU .

  Accordingly, in one embodiment, the present invention provides a method of treating cancer, wherein the method provides a patient with a therapeutically effective amount of one or more compounds of the present invention (eg, as shown herein). Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6 IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11 , IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Tables 1A and 1B, 2, 3A and 3B, and 4), or one or more compounds of the invention (eg, formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, as shown herein) , Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, Including administering a pharmaceutical composition comprising a compound of IVb8 and IVc, and a compound of Tables 1A and 1B, 2, 3A and 3B, and 4), and administering a therapeutically effective amount of L-1MT To do.

  Accordingly, in one embodiment, the present invention provides a method of treating cancer, wherein the method provides a patient with a therapeutically effective amount of one or more compounds of the present invention (eg, as shown herein). Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6 IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11 , IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Tables 1A and 1B, 2, 3A and 3B, and 4), or one or more compounds of the invention (eg, formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, as shown herein) , Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, Administering a pharmaceutical composition containing the compounds of IVb8 and IVc and the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4), and administering a therapeutically effective amount of methyl methanesulfonate (MMS) The process of carrying out is included.

  Accordingly, in one embodiment, the present invention provides a method of treating cancer, wherein the method provides a patient with a therapeutically effective amount of one or more compounds of the present invention (eg, as shown herein). Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6 IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11 , IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Tables 1A and 1B, 2, 3A and 3B, and 4), or one or more compounds of the invention (eg, formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, as shown herein) , Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, Administering a pharmaceutical composition containing the compounds of IVb8 and IVc and the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4) and administering a therapeutically effective amount of mechloretamine.

  Accordingly, in one embodiment, the present invention provides a method of treating cancer, wherein the method provides a patient with a therapeutically effective amount of one or more compounds of the present invention (eg, as shown herein). Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6 IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11 , IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Tables 1A and 1B, 2, 3A and 3B, and 4), or one or more compounds of the invention (eg, formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, as shown herein) , Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, Administering a pharmaceutical composition containing the compounds of IVb8 and IVc and the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4), and administering a therapeutically effective amount of streptozotocin.

  Accordingly, in one embodiment, the present invention provides a method of treating cancer, wherein the method provides a patient with a therapeutically effective amount of one or more compounds of the present invention (eg, as shown herein). Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6 IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11 , IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Tables 1A and 1B, 2, 3A and 3B, and 4), or one or more compounds of the invention (eg, formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, as shown herein) , Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, Administering a pharmaceutical composition comprising a compound of IVb8 and IVc, and a compound of Tables 1A and 1B, 2, 3A and 3B, and 4), and administering a therapeutically effective amount of raltitrexed.

  Accordingly, in one embodiment, the present invention provides a method of treating cancer, wherein the method provides a patient with a therapeutically effective amount of one or more compounds of the present invention (eg, as shown herein). Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6 IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11 , IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Tables 1A and 1B, 2, 3A and 3B, and 4), or one or more compounds of the invention (eg, formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, as shown herein) , Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, Administering a pharmaceutical composition containing the compounds of IVb8 and IVc and the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4), and administering a therapeutically effective amount of methotrexate.

  Accordingly, in one embodiment, the present invention provides a method of treating cancer, wherein the method provides a patient with a therapeutically effective amount of one or more compounds of the present invention (eg, as shown herein). Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6 IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11 , IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Tables 1A and 1B, 2, 3A and 3B, and 4), or one or more compounds of the invention (eg, formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, as shown herein) , Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, Administering a pharmaceutical composition comprising a compound of IVb8 and IVc, and a compound of Tables 1A and 1B, 2, 3A and 3B, and 4), and administering a therapeutically effective amount of bortezomib.

  Accordingly, in one embodiment, the present invention provides a method of treating cancer, wherein the method provides a patient with a therapeutically effective amount of one or more compounds of the present invention (eg, as shown herein). Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6 IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11 , IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Tables 1A and 1B, 2, 3A and 3B, and 4), or one or more compounds of the invention (eg, formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, as shown herein) , Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, Including administering a pharmaceutical composition comprising a compound of IVb8 and IVc, and a compound of Tables 1A and 1B, 2, 3A and 3B, and 4), and administering a therapeutically effective amount of PI-103 To do.

  Accordingly, in one embodiment, the present invention provides a method of treating cancer, wherein the method provides a patient with a therapeutically effective amount of one or more compounds of the present invention (eg, as shown herein). Formula I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6 IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11 , IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, IVb8, and IVc, and Tables 1A and 1B, 2, 3A and 3B, and 4), or one or more compounds of the invention (eg, formulas I, Ia, Ia1, Ia2, Ib, Ib1, Ib2, Ib3, Ic, as shown herein) , Id, II, IIa, IIa1, IIa2, IIa3, IIa4, IIb, IIb1, IIb2, IIb3, IIb4, IIb5, IIb6, IIb7, IIc, IIc1, IId, IId1, III, IIIa, IIIa1, IIIa2, IIIa3, IIIa4, IIIa5, IIIa6, IIIb, IIIb1, IIIb2, IIIb3, IIIb4, IIIb5, IIIb6, IIIb7, IIIb8, IIIb9, IIIb10, IIIb11, IIIc, IV, IVa, IVa1, IVa2, Iva3, IVa4, IVa5, IVa6, IVb, IVb1, IVb2, IVb3, IVb4, IVb5, IVb6, IVb7, Administering a pharmaceutical composition containing the compounds of IVb8 and IVc, and the compounds of Tables 1A and 1B, 2, 3A and 3B, and 4), and administering a therapeutically effective amount of dasatinib.

  In the case of combination therapy, a therapeutically effective amount of one or more other therapeutically effective compounds can be administered in a separate pharmaceutical composition, or the same pharmaceutical composition of the invention (one of the compounds of the invention). One). One or more of the compounds of the present invention are associated with cancer, systemic or chronic inflammation, rheumatoid arthritis, diabetes, obesity, T cell mediated autoimmune diseases, ischemia, and these diseases and disorders Can be administered together in the same formulation or dosage form in the same formulation as one or more other compounds that have been shown to be effective in the treatment of other complications. Accordingly, the present invention also provides an effective amount of one or more of the compounds of the present invention and an effective amount of at least one other compound (cancer, systemic or chronic inflammation, rheumatoid arthritis, diabetes, obesity , Which have been shown to be effective in the treatment of diseases, T cell mediated autoimmune diseases, ischemia, and other complications associated with these diseases and disorders) A composition or medicament is provided.

  The compounds of the present invention may also be synergistically treated or prevented for the same condition, as long as other active agents do not interfere with or adversely affect the effects of the compounds of the present invention, or otherwise in the patient to be treated. Can be administered in combination with another active agent that is effective against the disease or condition. Such other active agents include anti-inflammatory agents, antiviral agents, antibiotics, antifungal agents, antithrombotic agents, cardiovascular agents, cholesterol-lowering agents, anticancer agents, antihypertensive agents, and immune adjuvants, etc. However, it is not limited to these.

6. Methods for Making the Compounds of the Invention In a further aspect, the invention provides methods for making the compounds of the invention. Methods of making the compounds of the present invention and embodiments of intermediates used in these syntheses are provided in the following general synthetic schemes and specific synthetic processes. In all cases, these syntheses were initiated using commercially available starting materials.

  In some embodiments, the method of making the compound comprises:

を適切な条件下で反応させて、中間体

Reaction under appropriate conditions to produce an intermediate

を得る工程；
この中間体を第二の中間体

Obtaining
This intermediate is the second intermediate

に転換させる工程；
この第二の中間体をY-(CH₂)_q-NH₂と反応させて、

Converting to:
Reacting this second intermediate with Y- (CH ₂ ) _q -NH ₂ ,

を得る工程を包含し、ここでY、Y₁、o、p、およびqは、式IIIについて定義されたとおりであり、そしてR₁およびR₂は、式IIIa4またはIIIb5について定義されたとおりである。

Wherein Y, Y ₁ , o, p, and q are as defined for formula III, and R ₁ and R ₂ are as defined for formula IIIa4 or IIIb5. is there.

  In some embodiments, the method of making the compound comprises:

を適切な条件下で反応させて、中間体

Reaction under appropriate conditions to produce an intermediate

を得る工程；
この中間体を第二の中間体

Obtaining
This intermediate is the second intermediate

に転換させる工程；
この第二の中間体をY-(CH₂)_q-NH₂と反応させて、

Converting to:
Reacting this second intermediate with Y- (CH ₂ ) _q -NH ₂ ,

を得る工程を包含し、ここでY、Y₁、o、p、およびqは、式IIIについて定義されたとおりであり、そしてR₁、R₃、およびR₄は、式IIIa3またはIIIb4について定義されたとおりである。

Wherein Y, Y ₁ , o, p, and q are as defined for formula III, and R ₁ , R ₃ , and R ₄ are defined for formula IIIa3 or IIIb4 As it was done.

  Synthesis scheme

  Specific synthesis:

適切なアミン(1.0当量)を、適切なイソシアネート(1.0当量)のCH₂Cl₂中の溶液に、室温で滴下により添加した。その生成物を濾過により集め、そして減圧下で乾燥させた。

The appropriate amine (1.0 eq) was added dropwise at room temperature to a solution of the appropriate isocyanate (1.0 eq) in CH ₂ Cl ₂ . The product was collected by filtration and dried under reduced pressure.

R₆=Hについての手順。Pd/C(10%)を、適切なアリールニトロ化合物のメタノール中の混合物(約0.2M)に添加した。この反応混合物を排気し、そしてH₂(3×)で再度満たし、そしてH₂下(バルーン)で一晩撹拌した。この混合物をセライトで濾過し、そしてその濾液を濃縮して、所望の生成物を得た。

Procedure for R ₆ = H. Pd / C (10%) was added to a mixture of the appropriate aryl nitro compound in methanol (approximately 0.2M). The reaction mixture was evacuated and refilled with H ₂ (3 ×) and stirred under H ₂ (balloon) overnight. The mixture was filtered through celite and the filtrate was concentrated to give the desired product.

R ₆ = Procedure for some of the halogens. SnCl ₂ (3-6 eq) was added to a solution of the appropriate aryl nitro compound in EtOH or EtOAc and stirred at reflux for 4 hours to overnight. The solvent (if EtOH was used) was removed and the resulting residue was dissolved in EtOAc and washed with saturated NaHCO ₃ . The aqueous layer was extracted (twice) and the combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting residue was purified by Si-gel chromatography to give the desired product.

適切な塩化スルホニル(1.1当量)を、DIEA(DIEA=Huenig塩基、1.5当量)および適切なアミン(1.0当量)のDMF(約0.2M)中の溶液に添加した。この混合物を室温で一晩撹拌した。その溶媒を除去し、そして得られた残渣を水で洗浄した。この物質をMeOH/EtOAc中に懸濁させ、そしてその生成物を濾過により集め、そして減圧下で乾燥させた。必要であれば、この生成物をシリカゲルクロマトグラフィーにより精製した。

Appropriate sulfonyl chloride (1.1 equiv) was added to a solution of DIEA (DIEA = Huenig base, 1.5 equiv) and the appropriate amine (1.0 equiv) in DMF (ca. 0.2 M). The mixture was stirred at room temperature overnight. The solvent was removed and the resulting residue was washed with water. This material was suspended in MeOH / EtOAc and the product was collected by filtration and dried under reduced pressure. If necessary, the product was purified by silica gel chromatography.

適切な臭化アリール(1.0当量)、適切なボロン酸(1.5当量)、およびNa₂CO₃(2.8当量)の、DMF/水(10:1,0.2M)中の混合物を、N₂でフラッシュした。Pd(PPh₃)₄(0.07当量)を添加し、この混合物をN₂でフラッシュし、そして110℃で一晩撹拌した。この反応混合物を室温まで冷却し、そしてその不溶性物質を濾過により除去した。その濾液を濃縮し、そして得られた物質をシリカゲルクロマトグラフィーにより精製した。

A mixture of the appropriate aryl bromide (1.0 eq), the appropriate boronic acid (1.5 eq), and Na ₂ CO ₃ (2.8 eq) in DMF / water (10: 1, 0.2 M) is flushed with N ₂ did. Pd (PPh ₃ ) ₄ (0.07 eq) was added and the mixture was flushed with N ₂ and stirred at 110 ° C. overnight. The reaction mixture was cooled to room temperature and the insoluble material was removed by filtration. The filtrate was concentrated and the resulting material was purified by silica gel chromatography.

適切なアミンと適切な塩化スルホニルとの混合物を、ピリジン(約0.2M)中で室温で一晩撹拌した。このピリジンを除去し、そしてその残渣をEtOAcに溶解させ、そして1NのHClで洗浄した。その有機層をブラインで洗浄し、乾燥させ(Na₂SO₄)、濾過し、そして濃縮した。必要であれば、その生成物をシリカゲルクロマトグラフィーにより精製した。

A mixture of the appropriate amine and the appropriate sulfonyl chloride was stirred in pyridine (about 0.2M) at room temperature overnight. The pyridine was removed and the residue was dissolved in EtOAc and washed with 1N HCl. The organic layer was washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. If necessary, the product was purified by silica gel chromatography.

適切なアミン(1.0当量)およびEt₃N(3.2当量)のTHF中の溶液を、ホスゲン(COCl₂-トルエン中20%)のTHF(約0.2M)中の溶液に、0℃で滴下により添加した。この混合物を室温まで温め、そして1〜2時間撹拌した。この反応混合物をN₂でフラッシュし、そしてその溶媒を減圧下低温で除去して、過剰なCOCl₂を除去した。その残渣をTHF(0.2M)に溶解させ、第二の適切なアミンを添加し、そして得られた混合物を室温で一晩撹拌した。この混合物を濃縮し、そしてシリカゲルクロマトグラフィーにより精製した。

A solution of the appropriate amine (1.0 eq) and Et ₃ N (3.2 eq) in THF was added dropwise at 0 ° C. to a solution of phosgene (COCl ₂ -20% in toluene) in THF (ca.0.2 M). did. The mixture was warmed to room temperature and stirred for 1-2 hours. The reaction mixture was flushed with N ₂ and the solvent was removed at low temperature under reduced pressure to remove excess COCl ₂ . The residue was dissolved in THF (0.2M), a second appropriate amine was added, and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated and purified by silica gel chromatography.

適切なアミノピリジン(1.0当量)を、適切なクロロイソシアネート(1.0当量)のCH₂Cl₂(約0.2M)中の溶液に、0℃で滴下により添加した。得られた混合物を0℃で45分間撹拌した。その固体生成物を濾過により集め、そして減圧下で乾燥させた。

Appropriate aminopyridine (1.0 eq) was added dropwise at 0 ° C. to a solution of the appropriate chloroisocyanate (1.0 eq) in CH ₂ Cl ₂ (˜0.2 M). The resulting mixture was stirred at 0 ° C. for 45 minutes. The solid product was collected by filtration and dried under reduced pressure.

適切なフェノール(1.1当量)およびCs₂CO₃(1.5当量)の、DMF(約0.2M)中の混合物を、室温で45分間撹拌した。適切な塩化物(1.0当量)を添加し、そしてこの反応混合物を80℃で一晩撹拌した。この混合物を室温まで冷却した。その不溶性物質を濾過により除去し、そしてその濾液を濃縮した。得られた残渣をシリカゲルクロマトグラフィーにより精製した。

A mixture of the appropriate phenol (1.1 eq) and Cs ₂ CO ₃ (1.5 eq) in DMF (ca. 0.2 M) was stirred at room temperature for 45 min. Appropriate chloride (1.0 eq) was added and the reaction mixture was stirred at 80 ° C. overnight. The mixture was cooled to room temperature. The insoluble material was removed by filtration and the filtrate was concentrated. The resulting residue was purified by silica gel chromatography.

DIEA(3当量)を、適切なアミン、適切な安息香酸、DIC(1.2当量)およびヒドロキシベンゾトリアゾール（Hydroxyvenzotriazole）(HOBt)(1.2当量)のDMF中の混合物に添加した。この混合物を室温で一晩撹拌した。この溶液を濃縮し、そして逆相(RP)-HPLCにより精製した。

DIEA (3 eq) was added to a mixture of the appropriate amine, appropriate benzoic acid, DIC (1.2 eq) and hydroxybenzotriazole (HOBt) (1.2 eq) in DMF. The mixture was stirred at room temperature overnight. The solution was concentrated and purified by reverse phase (RP) -HPLC.

DEAD(1.2当量,PhCH₃中2M)を、DCMまたはTHF中の適切なフェノール、適切なアミノアルコール、およびPPh₃(1.2当量)の混合物に、0℃で添加した。この溶液を室温まで温め、そして一晩撹拌し、濃縮し、そしてシリカゲルクロマトグラフィーにより精製した。

DEAD (1.2 eq, 2M in PhCH ₃ ) was added to a mixture of the appropriate phenol, the appropriate amino alcohol, and PPh ₃ (1.2 eq) in DCM or THF at 0 ° C. The solution was warmed to room temperature and stirred overnight, concentrated and purified by silica gel chromatography.

Alternatively, a suitable N-boc-aminoalcohol can be used in the above procedure, followed by TFA / DCM deprotection as follows: TFA (approximately 3 mL / mmol) is added to this N-boc- The amine was added and the solution was stirred at room temperature for 30 minutes. The solution was concentrated and dissolved in EtOAc, washed with saturated NaHCO ₃ , dried over Na ₂ SO ₄ , concentrated and, if necessary, purified by silica gel chromatography.

DEAD(1.2当量,PhCH₃中2M)を0℃で、DCM中の適切なチオール、適切なアルコール、およびPPh₃(1.2当量)に添加した。この溶液を室温で一晩撹拌し、濃縮し、そしてシリカゲルクロマトグラフィーにより精製した。

DEAD (1.2 eq, 2M in PhCH ₃ ) was added at 0 ° C. to the appropriate thiol, the appropriate alcohol, and PPh ₃ (1.2 eq) in DCM. The solution was stirred overnight at room temperature, concentrated and purified by silica gel chromatography.

m-CPBA(2.2当量)をDCM中の適切なスルフィドに添加し、そしてこの混合物を室温で２時間撹拌した。この得られたスルホキシドとスルホンとの混合物を濃縮し、そしてRP-HPLCにより精製した。

m-CPBA (2.2 eq) was added to the appropriate sulfide in DCM and the mixture was stirred at room temperature for 2 hours. The resulting mixture of sulfoxide and sulfone was concentrated and purified by RP-HPLC.

4-フルオロ-1-ニトロベンゼン、適切なチオール、およびK₂CO₃(3当量)を、DMF中60℃で64時間加熱した。この溶液をEtOAcで希釈し、10%のHClで洗浄し、Na₂SO₄で乾燥させ、そして濃縮して、所望の生成物を得た。

4-Fluoro-1-nitrobenzene, the appropriate thiol, and K ₂ CO ₃ (3 eq) were heated in DMF at 60 ° C. for 64 hours. The solution was diluted with EtOAc, washed with 10% HCl, dried over Na ₂ SO ₄ and concentrated to give the desired product.

DEAD(1.2当量,PhCH₃中2M)を、0℃で、DCM中の適切なフェノール、適切なグリコール酸メチル、およびPPh₃(1.2当量)の混合物に添加した。この溶液を室温で一晩撹拌し、濃縮し、そしてシリカゲルクロマトグラフィーにより精製した。

DEAD (1.2 eq, 2M in PhCH ₃ ) was added at 0 ° C. to a mixture of the appropriate phenol, the appropriate methyl glycolate, and PPh ₃ (1.2 eq) in DCM. The solution was stirred overnight at room temperature, concentrated and purified by silica gel chromatography.

適切なエステルをメタノールに溶解させ、その後、NaOH(10%,2.5当量)を添加した。この混合物を室温で4時間撹拌し、酸性化し、そして酢酸エチルで抽出した。濃縮後、この酸をさらに精製せずに使用した。

The appropriate ester was dissolved in methanol and then NaOH (10%, 2.5 eq) was added. The mixture was stirred at room temperature for 4 hours, acidified and extracted with ethyl acetate. After concentration, the acid was used without further purification.

適切なカルボン酸をDCMに溶解させ、そして塩化オキサリルを添加した。室温で30分間撹拌した後に、この混合物を濃縮し、そして得られた酸塩化物をそのまま引き続く反応に使用した。

The appropriate carboxylic acid was dissolved in DCM and oxalyl chloride was added. After stirring at room temperature for 30 minutes, the mixture was concentrated and the resulting acid chloride was used as such for the subsequent reaction.

Appropriate mono-BOC protected diamine (1 eq) was added to a solution of the crude acid chloride (1 eq) and Et ₃ N (3 eq) obtained above in DCM. After the mixture was stirred at room temperature overnight, the mixture was washed with HCl (1N) and the organic layer was concentrated and used without further purification.

適切なモノ-N-boc-ジアミン(1.2当量)を、DCE中の適切な塩化スルホニル、DIEA(1.5当量)に添加し、そしてこの溶液を室温で90分間撹拌した。10%のHClおよびDCMを添加し、そしてその有機層をNa₂SO₄で乾燥させたか、または相分離カラムを使用して乾燥させ、そして濃縮した。TFAおよびDCMを添加し、そしてこの溶液を室温で30〜60分間撹拌し、そして濃縮した。

Appropriate mono-N-boc-diamine (1.2 eq) was added to the appropriate sulfonyl chloride in DCE, DIEA (1.5 eq) and the solution was stirred at room temperature for 90 min. 10% HCl and DCM were added and the organic layer was dried over Na ₂ SO ₄ or dried using a phase separation column and concentrated. TFA and DCM were added and the solution was stirred at room temperature for 30-60 minutes and concentrated.

ジホスゲン(0.6当量)およびEt₃N(1.2当量)を、DCM中の適切なアミンに0℃で添加し、そしてこの溶液を0℃で20〜120分間撹拌した。Et₃N(3当量)および第二の適切なアミン(1.2当量)を0℃で添加し、そしてこの溶液を室温まで一晩温めた。この溶液を濃縮し、そしてシリカゲルクロマトグラフィーまたはRP-HPLCにより精製した。

Diphosgene (0.6 eq) and Et ₃ N (1.2 eq) were added to the appropriate amine in DCM at 0 ° C. and the solution was stirred at 0 ° C. for 20-120 min. Et ₃ N (3 eq) and a second appropriate amine (1.2 eq) were added at 0 ° C. and the solution was allowed to warm to room temperature overnight. The solution was concentrated and purified by silica gel chromatography or RP-HPLC.

DIAD(アゾジカルボン酸ジイソプロピル)(2.0当量)を、適切なスルホンアミド(1.0当量)、メタノール(2.0当量)、およびPPh₃(2.0当量)のTHF(0.2M)中の混合物に、滴下により0℃で添加した。添加後、この混合物を室温まで温め、そして一晩撹拌した。その溶媒を除去し、そして得られた溶液を濃縮し、そしてシリカゲルクロマトグラフィーにより精製した。

DIAD (diisopropyl azodicarboxylate) (2.0 eq) was added dropwise to a mixture of the appropriate sulfonamide (1.0 eq), methanol (2.0 eq), and PPh ₃ (2.0 eq) in THF (0.2 M) dropwise. Added at. After the addition, the mixture was warmed to room temperature and stirred overnight. The solvent was removed and the resulting solution was concentrated and purified by silica gel chromatography.

クロロスルホン酸(4.10mL,62.6mmol)を、2,3-ジメチルキナゾリン-4(3H)-オン(1.09g,0.26mmo)にゆっくりと添加した。得られた混合物を140℃までゆっくりと温め、そして同じ温度で3時間撹拌した。室温まで冷却した後に、その粘性の反応混合物を砕いた氷に注いだ。その沈殿物を濾過により集め、H₂Oで洗浄し、そして減圧下で乾燥させて、所望の化合物を得た。

Chlorosulfonic acid (4.10 mL, 62.6 mmol) was slowly added to 2,3-dimethylquinazolin-4 (3H) -one (1.09 g, 0.26 mmo). The resulting mixture was slowly warmed to 140 ° C. and stirred at the same temperature for 3 hours. After cooling to room temperature, the viscous reaction mixture was poured onto crushed ice. The precipitate was collected by filtration, washed with H ₂ O and dried under reduced pressure to give the desired compound.

適切なアミン(0.495mmol)のDMF(1mL)中の溶液に、ピリジン(2.06mmol)、2,3-ジメチル-4-オキソ-3,4-ジヒドロキナゾリン-6-スルホニルクロリド(0.495mmol)、およびDMAP(0.041mmol)を0℃で順番に添加した。この混合物を室温で10時間撹拌した後に、その沈殿物を濾過により除去し、そしてMeOHで洗浄した。合わせた濾液を減圧中で濃縮し、そして分取HPLCにより精製して、表題化合物をTFA塩として得た。

To a solution of the appropriate amine (0.495 mmol) in DMF (1 mL), pyridine (2.06 mmol), 2,3-dimethyl-4-oxo-3,4-dihydroquinazoline-6-sulfonyl chloride (0.495 mmol), and DMAP (0.041 mmol) was added sequentially at 0 ° C. After the mixture was stirred at room temperature for 10 hours, the precipitate was removed by filtration and washed with MeOH. The combined filtrate was concentrated in vacuo and purified by preparative HPLC to give the title compound as a TFA salt.

バイアル中の適切なフルオロフェニルスルホンアミド(0.13mmol)および適切なアミン(0.50mL)の混合物を、100℃で撹拌しながら一晩加熱した。この混合物を減圧下で濃縮し、次いで、さらなるフルオロフェニルスルホンアミド(0.50mL)を添加し、そして再度、100℃で撹拌しながら一晩加熱した。この混合物を減圧下で濃縮し、そしてHPLCを使用することにより精製して、所望の生成物を得た。

A mixture of the appropriate fluorophenylsulfonamide (0.13 mmol) and the appropriate amine (0.50 mL) in the vial was heated at 100 ° C. with stirring overnight. The mixture was concentrated under reduced pressure, then additional fluorophenylsulfonamide (0.50 mL) was added and again heated at 100 ° C. with stirring overnight. The mixture was concentrated under reduced pressure and purified by using HPLC to give the desired product.

塩化オキサリル(1.2当量)を、DCM(0.2M)中の適切なアミンに添加し、そしてこの溶液を室温で15分間撹拌した。第二の適切なアミン(1.5当量)およびEt₃N(2当量)をDMF(1mL)中で添加し、そしてこの溶液を周囲温度で一晩撹拌した。この混合物を濃縮し、そしてRP-HPLCにより精製した。

Oxalyl chloride (1.2 eq) was added to the appropriate amine in DCM (0.2 M) and the solution was stirred at room temperature for 15 minutes. A second appropriate amine (1.5 eq) and Et ₃ N (2 eq) were added in DMF (1 mL) and the solution was stirred overnight at ambient temperature. The mixture was concentrated and purified by RP-HPLC.

DIEA(3当量)を、DCM(0.2M)中の適切なカルボン酸、H-Ser-OMe、EDCI(1.2当量)およびHOBt(1.2当量)に添加し、そしてこの溶液を室温で一晩撹拌した。この溶液を10%(aq)HCl、飽和NaHCO₃で洗浄し、Na₂SO₄で乾燥させ、濃縮し、そしてシリカゲルクロマトグラフィー(0〜60% EtOAc/hex)により精製した。得られた油状物にTHF(0.2M)およびLawesson試薬(1.2当量)を添加し、次いで、この溶液を一晩加熱還流し、濃縮し、そしてシリカゲルクロマトグラフィー(0〜60% EtOAc/hex)により精製した。

DIEA (3 eq) was added to the appropriate carboxylic acid, H-Ser-OMe, EDCI (1.2 eq) and HOBt (1.2 eq) in DCM (0.2 M) and the solution was stirred at room temperature overnight. . The solution was washed with 10% (aq) HCl, saturated NaHCO ₃ , dried over Na ₂ SO ₄ , concentrated, and purified by silica gel chromatography (0-60% EtOAc / hex). To the resulting oil was added THF (0.2 M) and Lawesson reagent (1.2 eq), then the solution was heated to reflux overnight, concentrated and purified by silica gel chromatography (0-60% EtOAc / hex). Purified.

BrCCl₃(1.1当量)を、DCM(0.15M)中の適切なエステルおよびDBU(1.1当量)に添加し、そしてこの溶液を室温で90分間撹拌した。この溶液をさらなるDCMで希釈し、10%のHClで洗浄し、Na₂SO₄で乾燥させ、そして濃縮した。得られた物質に、LiCl(1.2当量)およびMeOH(0.2M)を添加した。NaBH₄(1.2当量)を添加し、そしてこの溶液を室温で一晩撹拌した。さらなるLiCl/NaBH₄(1.2当量ずつ)を添加し、そしてこの溶液を一晩撹拌した。この混合物をEtOAcで希釈し、10%(aq)HClで洗浄し、Na₂SO₄で乾燥させ、そして濃縮した。得られた物質をシリカゲルクロマトグラフィー(0〜100% EtOAc/hex)により精製した。

BrCCl ₃ (1.1 equiv) was added to the appropriate ester and DBU (1.1 equiv) in DCM (0.15 M) and the solution was stirred at room temperature for 90 min. The solution was diluted with additional DCM, washed with 10% HCl, dried over Na ₂ SO ₄ and concentrated. To the resulting material was added LiCl (1.2 eq) and MeOH (0.2 M). NaBH ₄ (1.2 eq) was added and the solution was stirred overnight at room temperature. Additional LiCl / NaBH ₄ (1.2 equivalent portions) was added and the solution was stirred overnight. The mixture was diluted with EtOAc, washed with 10% (aq) HCl, dried over Na ₂ SO ₄ and concentrated. The resulting material was purified by silica gel chromatography (0-100% EtOAc / hex).

DEAD(PhCH₃中2M,1.2当量)を、THF(0.2M)中のジフェニルホスホリルアジド(DPPA)(1.2当量)、PPh₃(1.2当量)およびピリジン(1.2当量)に、0℃でゆっくりと添加した。この溶液を0℃で5分間撹拌した。適切なアルコールを少量のTHF中で添加し、そしてこの溶液を一晩、室温まで温めた。この溶液を濃縮し、そしてシリカゲルクロマトグラフィー(0〜100% EtOAc/hex)により精製した。得られた油状物にPPh₃(1.2当量)およびTHF(0.2M)を添加し、次いでこの溶液を30分間撹拌した。水(THFの10%体積)を添加し、そしてこの混合物を一晩加熱還流し、濃縮し、そしてシリカゲルクロマトグラフィー(0〜15% MeOH/DCM)により精製した。

DEAD (PhCH ₃ in 2M, 1.2 eq), in THF diphenylphosphoryl azide in (0.2 M) (DPPA) (1.2 equiv), PPh ₃ (1.2 eq) and pyridine (1.2 eq), added slowly at 0 ℃ did. The solution was stirred at 0 ° C. for 5 minutes. Appropriate alcohol was added in a small amount of THF and the solution was allowed to warm to room temperature overnight. The solution was concentrated and purified by silica gel chromatography (0-100% EtOAc / hex). To the resulting oil was added PPh ₃ (1.2 eq) and THF (0.2 M), then the solution was stirred for 30 min. Water (10% volume of THF) was added and the mixture was heated to reflux overnight, concentrated and purified by silica gel chromatography (0-15% MeOH / DCM).

適切なアミン(1.0当量)を、適切な塩化スルホニル-イソシアネート(1.0当量)のCH₂Cl₂中の溶液に、滴下により0℃で添加した。この反応混合物を撹拌しながら一晩、室温まで温めた。この混合物を減圧下で濃縮し、そしてRP-HPLCを使用して精製して、所望の生成物を得た。

The appropriate amine (1.0 eq) was added dropwise at 0 ° C. to a solution of the appropriate sulfonyl chloride-isocyanate (1.0 eq) in CH ₂ Cl ₂ . The reaction mixture was allowed to warm to room temperature overnight with stirring. The mixture was concentrated under reduced pressure and purified using RP-HPLC to give the desired product.

丸底フラスコ中で、4-アミノ-6-クロロ-ベンゼン-1,3-ジスルホンアミド(11.4g,39.89mmol)を撹拌しながらギ酸(150mL)に添加した。この反応混合物を撹拌しながら125℃で加熱した(48時間)。この溶液を冷却し、白色沈殿物が形成されるまで、水を添加した。この沈殿物を濾過により集め、乾燥させ、そしてさらに精製せずに持ち越して、所望の生成物を得た。

In a round bottom flask, 4-amino-6-chloro-benzene-1,3-disulfonamide (11.4 g, 39.89 mmol) was added to formic acid (150 mL) with stirring. The reaction mixture was heated at 125 ° C. with stirring (48 hours). The solution was cooled and water was added until a white precipitate was formed. The precipitate was collected by filtration, dried and carried forward without further purification to give the desired product.

丸底フラスコ中で、6-クロロ-1,1-ジオキソ-2H-ベンゾ[e][1,2,4]チアジアジン-7-スルホンアミド(7.4g,25.02mmol)を添加した。これに、クロロスルホン酸(37.5mL)をゆっくりと添加した。添加が完了したら、この反応混合物を100℃で2時間加熱した。この混合物を室温まで冷却し、次いで注意深くゆっくりと、氷に注いだ。所望の生成物を、濾過により、白色固体として単離した。

In a round bottom flask, 6-chloro-1,1-dioxo-2H-benzo [e] [1,2,4] thiadiazine-7-sulfonamide (7.4 g, 25.02 mmol) was added. To this was added chlorosulfonic acid (37.5 mL) slowly. Once the addition was complete, the reaction mixture was heated at 100 ° C. for 2 hours. The mixture was cooled to room temperature and then poured slowly and slowly into ice. The desired product was isolated as a white solid by filtration.

丸底フラスコ中で、アセトアミジンHCl(1.46g,15.41mmol,1.1当量)をEtOH(50mL)中で撹拌しながら、1-tert-ブチル-3-エチル-4-オキソピペリジン-1,3-ジカルボキシレート(3.8g,14.01mmol)を添加した。撹拌中に、固体の金属ナトリウム(0.71g,29.42mmol,2.1当量)を添加した。溶解したら、この反応混合物を100℃で、週末をまたいで加熱した。この反応混合物を冷却し、そして濾過して固体を除去した。次いで、このEtOH溶液を濃縮して、所望の生成物をクリーム色の固体として得た。

In a round bottom flask, acetamidine HCl (1.46 g, 15.41 mmol, 1.1 eq) was stirred in EtOH (50 mL) while stirring 1-tert-butyl-3-ethyl-4-oxopiperidine-1,3-diethyl. Carboxylate (3.8 g, 14.01 mmol) was added. During stirring, solid metallic sodium (0.71 g, 29.42 mmol, 2.1 eq) was added. Once dissolved, the reaction mixture was heated at 100 ° C. over the weekend. The reaction mixture was cooled and filtered to remove solids. The EtOH solution was then concentrated to give the desired product as a cream solid.

大きいバイアルに、2-メチル-4-オキソ-3,5,7,8-テトラヒドロピリド[4,3-d]ピリミジン-6-カルボン酸tert-ブチル(1.5g,5.65mmol)を添加し、そしてDMF(15mL,無水)に溶解させた。炭酸セシウム(2.76g,8.48mmol)およびヨードメタン(0.39mL,6.12mmol)を添加し、そしてこの混合物を室温で撹拌した(4時間)。LCMSは、主要なピークが所望の生成物であることを示した。この反応混合物をSiO₂上で濃縮し、そしてシリカゲルクロマトグラフィー(0〜20% DCM/MeOH)により精製した。

To a large vial was added tert-butyl 2-methyl-4-oxo-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6-carboxylate (1.5 g, 5.65 mmol); Then, it was dissolved in DMF (15 mL, anhydrous). Cesium carbonate (2.76 g, 8.48 mmol) and iodomethane (0.39 mL, 6.12 mmol) were added and the mixture was stirred at room temperature (4 hours). LCMS showed that the main peak was the desired product. The reaction mixture was concentrated on SiO ₂ and purified by silica gel chromatography (0-20% DCM / MeOH).

丸底フラスコ中で、2,3-ジメチル-4-オキソ-7,8-ジヒドロ-5H-ピリド[4,3-d]ピリミジン-6-カルボン酸tert-ブチル(1.0g,3.58mmol)を、DCM(10mL)およびTFA(5mL)またはHClジオキサン(4M,10〜20当量)中に室温で添加し、撹拌した(2時間)。濃縮して所望の生成物を得、そして精製せずに持ち越した。

In a round bottom flask, tert-butyl 2,3-dimethyl-4-oxo-7,8-dihydro-5H-pyrido [4,3-d] pyrimidine-6-carboxylate (1.0 g, 3.58 mmol) Added in DCM (10 mL) and TFA (5 mL) or HCl dioxane (4M, 10-20 eq) at room temperature and stirred (2 h). Concentration gave the desired product and carried forward without purification.

適切なエステル(1.14g,3.81mmol)を、LiOH(1N,10mL)およびTHF(10mL)中に室温で添加し、一晩撹拌した。この混合物を濃縮して溶媒を除去し、そして20%のMeOH/DCMに再溶解させ、濾過して固体を除去した。その母液を濃縮して、所望の生成物を白色固体として得た。

The appropriate ester (1.14 g, 3.81 mmol) was added in LiOH (1N, 10 mL) and THF (10 mL) at room temperature and stirred overnight. The mixture was concentrated to remove the solvent and redissolved in 20% MeOH / DCM and filtered to remove the solid. The mother liquor was concentrated to give the desired product as a white solid.

TEA(3.0当量)を、DMF中の適切なアニリン、適切な安息香酸(1.1当量)、EDC(1.5当量)およびHOBt(1.5当量)の混合物に添加した。この混合物を室温で一晩撹拌した。この溶液を濃縮し、そして逆相(RP)-HPLCにより精製した。

TEA (3.0 eq) was added to a mixture of the appropriate aniline, appropriate benzoic acid (1.1 eq), EDC (1.5 eq) and HOBt (1.5 eq) in DMF. The mixture was stirred at room temperature overnight. The solution was concentrated and purified by reverse phase (RP) -HPLC.

適切なアニリン(1.0当量)および適切なベンズアルデヒド(1.3当量)のDCE(0.2M)中の混合物に、Na(OAc)₃BH(1.5当量)を添加し、続いてAcOH(2〜4滴)を添加した。得られた混合物を室温で一晩撹拌した。この反応を、10%のNaOH(溶媒体積に等しい量)の添加によりクエンチし、その層を分離し、そしてその有機層を濃縮し、そして逆相クロマトグラフィーにより精製した。

To a mixture of the appropriate aniline (1.0 eq) and the appropriate benzaldehyde (1.3 eq) in DCE (0.2 M) is added Na (OAc) ₃ BH (1.5 eq) followed by AcOH (2-4 drops). Added. The resulting mixture was stirred overnight at room temperature. The reaction was quenched by the addition of 10% NaOH (an amount equal to the solvent volume), the layers were separated and the organic layer was concentrated and purified by reverse phase chromatography.

ヨードメタン(1.2当量)を、DMF(0.5M)中の適切なカルボン酸およびK₂CO₃(3当量)に添加した。この混合物を室温で一晩撹拌した。酢酸エチルを添加し、この溶液を10%(aq)HCl、水、およびブラインで洗浄し、Na₂SO₄で乾燥させ、そして濃縮した。得られた固体をTHF(0.2M)に溶解させた。Ti(OPrⁱ)₄(1.05当量)を添加し、続いてEtMgBr(Et₂O中3.0M,5当量)を添加した。得られた溶液を室温で一晩撹拌した。飽和NH₄Clを添加し、この溶液をセライトで濾過し、そして濾過した固体をDCMで洗浄した。その濾液の層を分離し、そしてその有機層をNa₂SO₄で乾燥させ、濃縮し、そして勾配シリカゲルクロマトグラフィー(0〜30% EtOAc/hex)により精製した。

Iodomethane (1.2 eq) was added to the appropriate carboxylic acid and K ₂ CO ₃ (3 eq) in DMF (0.5 M). The mixture was stirred at room temperature overnight. Ethyl acetate was added and the solution was washed with 10% (aq) HCl, water, and brine, dried over Na ₂ SO ₄ and concentrated. The resulting solid was dissolved in THF (0.2M). Ti (OPr ⁱ ) ₄ (1.05 eq) was added followed by EtMgBr (3.0 M in Et ₂ O, 5 eq). The resulting solution was stirred overnight at room temperature. Saturated NH ₄ Cl was added, the solution was filtered through celite, and the filtered solid was washed with DCM. The filtrate layers were separated and the organic layer was dried over Na ₂ SO ₄ , concentrated and purified by gradient silica gel chromatography (0-30% EtOAc / hex).

大きいバイアルに、適切な臭化ベンジルをDMF(1.0M)に溶解させた。これに適切なアルコール(1.0当量)およびK₂CO₃(2.0当量)を添加した。この反応物を60℃で一晩加熱した。粗製反応混合物をSiO₂上で濃縮し、そして勾配シリカゲルクロマトグラフィー（0〜20% EtOAc/Hex）により精製した。

In a large vial, the appropriate benzyl bromide was dissolved in DMF (1.0 M). To this was added the appropriate alcohol (1.0 eq) and K ₂ CO ₃ (2.0 eq). The reaction was heated at 60 ° C. overnight. The crude reaction mixture was concentrated on SiO ₂ and purified by gradient silica gel chromatography (0-20% EtOAc / Hex).

適切なアミン(1.0当量)、適切な安息香酸(1.2当量)、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド(EDCI)(1.3当量)、HOBT(1.3当量)およびDIEA(4.0当量)の、DMF(0.2M)中の混合物を室温で一晩撹拌した。この反応混合物を濃縮し、そして逆相クロマトグラフィーにより精製した。

Appropriate amine (1.0 eq), appropriate benzoic acid (1.2 eq), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) (1.3 eq), HOBT (1.3 eq) and DIEA (4.0 eq) Of DMF (0.2M) was stirred overnight at room temperature. The reaction mixture was concentrated and purified by reverse phase chromatography.

所望のアルコール(1.2当量)のDMF中の溶液に、K₂CO₃(3.0当量)を添加し、続いて所望のフタルイミド（thalimide）保護アミノアルコール(1.0当量)を添加した。この反応物を80℃で24時間加熱した。水を添加し、そしてその沈殿物を濾過して所望の生成物を得、これを減圧下で乾燥させた。

To a solution of the desired alcohol (1.2 eq) in DMF was added K ₂ CO ₃ (3.0 eq) followed by the desired phthalimide protected aminoalcohol (1.0 eq). The reaction was heated at 80 ° C. for 24 hours. Water was added and the precipitate was filtered to give the desired product, which was dried under reduced pressure.

フタルイミド（thalimide）保護アミン(9.0g)に、無水ヒドラジン(20ml)を添加した。この混合物を室温で18時間撹拌した。アセトニトリルを添加し、そして得られた固体を濾過した。その濾液を濃縮した。水での後処理を行った。その有機層をNa₂S₂O₄で乾燥させ、濾過し、そして減圧下で濃縮して、所望の生成物を得た。

To phthalimide protected amine (9.0 g) was added anhydrous hydrazine (20 ml). The mixture was stirred at room temperature for 18 hours. Acetonitrile was added and the resulting solid was filtered. The filtrate was concentrated. Work-up with water was carried out. The organic layer was dried over Na ₂ S ₂ O ₄ , filtered and concentrated under reduced pressure to give the desired product.

トリイソプロピルシリルクロリド(TIPSCl)(1.2当量)を、DCM中の適切なジアルコール(1当量)およびEt₃N(1.5当量)に添加した。この溶液を室温で2時間撹拌し、10%のHClで洗浄し、Na₂SO₄で乾燥させ、濃縮し、そしてシリカゲルクロマトグラフィーにより精製して、所望の生成物を得た。

Triisopropylsilyl chloride (TIPSCl) (1.2 eq) was added to the appropriate dialcohol (1 eq) and Et ₃ N (1.5 eq) in DCM. The solution was stirred at room temperature for 2 hours, washed with 10% HCl, dried over Na ₂ SO ₄ , concentrated, and purified by silica gel chromatography to give the desired product.

DMF(1mL/mmol)を、所望のアルコール(1当量)および適切な臭化物(1当量)に添加した。K₂CO₃(3当量)を添加し、そしてこの溶液を60℃で3時間加熱した。この溶液を冷却し、EtOAc(DMFの約5倍の体積)で希釈し、そして10%のHCl、水、およびブライン(それぞれDMFの3〜5倍の体積)で洗浄した。その有機層をNa₂SO₄で乾燥させ、濾過し、そして濃縮した。

DMF (1 mL / mmol) was added to the desired alcohol (1 eq) and the appropriate bromide (1 eq). K ₂ CO ₃ (3 eq) was added and the solution was heated at 60 ° C. for 3 hours. The solution was cooled, diluted with EtOAc (about 5 times the volume of DMF) and washed with 10% HCl, water, and brine (3-5 times each volume of DMF). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated.

MeOHまたはEtOH(1mL/mmol)を、置換エステルに添加した。NaOH(10% w/w水性,1mL/mmol,約2.5当量)を添加し、そしてこの溶液を1時間加熱還流した。後処理A:この溶液を冷却し、EtOAc(MeOHの約5倍の体積)で希釈し、そして10%のHClで洗浄した。その有機層をNa₂SO₄で乾燥させ、濾過し、そして濃縮した。得られた固体をEtOAcで粉砕して、残留フェノールを除去した。

MeOH or EtOH (1 mL / mmol) was added to the substituted ester. NaOH (10% w / w aqueous, 1 mL / mmol, ca. 2.5 equiv) was added and the solution was heated to reflux for 1 h. Work-up A: The solution was cooled, diluted with EtOAc (approximately 5 times the volume of MeOH) and washed with 10% HCl. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The resulting solid was triturated with EtOAc to remove residual phenol.

  Workup B: The solution was cooled and the solvent was removed under reduced pressure. The resulting residue was dissolved in water and acidified to about pH2. The precipitate was collected by filtration and dried under reduced pressure.

ジフェニルホスホリルアジド(DPPA)(1当量)を、トルエン(0.2M)中の置換カルボン酸およびEt₃N(1当量)に添加し、そしてその溶液を2時間加熱還流した。この反応混合物を室温まで冷却し、適切なアミン(1.2当量)を添加し、そしてこの溶液を室温で2〜3時間撹拌した。この溶液をシリカゲル上で濃縮し、そしてシリカゲルクロマトグラフィー(0〜15% MeOH/DCM)により精製した。得られた黄色油状物を最小量のDCMに溶解させ、大過剰のヘキサンに添加し、0.5〜2時間撹拌し、そしてその生成物を濾過した。

Diphenylphosphoryl azide (DPPA) (1 eq) was added to the substituted carboxylic acid and Et ₃ N (1 eq) in toluene (0.2 M) and the solution was heated to reflux for 2 h. The reaction mixture was cooled to room temperature, the appropriate amine (1.2 eq) was added, and the solution was stirred at room temperature for 2-3 hours. The solution was concentrated on silica gel and purified by silica gel chromatography (0-15% MeOH / DCM). The resulting yellow oil was dissolved in a minimum amount of DCM, added to a large excess of hexane, stirred for 0.5-2 hours, and the product was filtered.

適切なイソシアネート(1当量)の2-メチルテトラヒドロフラン中の溶液に、適切なアミン(1.2当量)を添加した。この混合物を65℃で18時間加熱した。この混合物を濃縮し、そして逆相HPLCにより精製した。

To a solution of the appropriate isocyanate (1 eq) in 2-methyltetrahydrofuran was added the appropriate amine (1.2 eq). The mixture was heated at 65 ° C. for 18 hours. The mixture was concentrated and purified by reverse phase HPLC.

ジクロロエタン(2mL)中の適切なアルデヒド(0.12mmol)に、所望のアミン(0.23mmol)およびジイソプロピルエチルアミン(0.23mmol)を添加した。5分間撹拌した後に、トリアセトキシ水素化ホウ素ナトリウム(0.23mmol)をこの混合物に添加した。LCMSにより決定する場合にこの反応が完了したら、この反応をMeOH(5mL)の添加によりクエンチした。この反応物を濃縮し、そして逆相(RP)-HPLCにより精製した。

To the appropriate aldehyde (0.12 mmol) in dichloroethane (2 mL) was added the desired amine (0.23 mmol) and diisopropylethylamine (0.23 mmol). After stirring for 5 minutes, sodium triacetoxyborohydride (0.23 mmol) was added to the mixture. When the reaction was complete as determined by LCMS, the reaction was quenched by the addition of MeOH (5 mL). The reaction was concentrated and purified by reverse phase (RP) -HPLC.

丸底フラスコ中で、2-メチル-4-オキソ-3,5,7,8-テトラヒドロピリド[4,3-d]ピリミジン-6-カルボン酸tert-ブチル(2.0g,7.54mmol)をDCMに溶解させ、続いてTEA(1.2当量)およびDMAP(0.1当量)を添加した。この混合物を室温で一晩撹拌した。この混合物を予め充填したシリカに注ぎ、そしてシリカゲルクロマトグラフィー(0〜10% DCM/MeOH)により精製した。所望の生成物を粘着性の白色固体(2.73g,86%)として単離した。

In a round bottom flask, tert-butyl 2-methyl-4-oxo-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6-carboxylate (2.0 g, 7.54 mmol) was DCM. Followed by the addition of TEA (1.2 eq) and DMAP (0.1 eq). The mixture was stirred at room temperature overnight. The mixture was poured onto pre-filled silica and purified by silica gel chromatography (0-10% DCM / MeOH). The desired product was isolated as a sticky white solid (2.73 g, 86%).

丸底フラスコ中に、2-メチル-4-(p-トリルスルホニルオキシ)-7,8-ジヒドロ-5H-ピリド[4,3-d]ピリミジン-6-カルボン酸tert-ブチル(2.73g,6.51mmol)を、適切なボロン酸(3.0当量)、K₃PO₄(6.0当量)、および2-ジシクロヘキシルホスフィノ-ビフェニル(0.1当量)と一緒に添加し、続いて窒素でスパージした(10分間)。この混合物にジオキサン(100mL)およびH₂O(1.0mL)を添加した。再度、この混合物を窒素でスパージした(5分間)。Pd(OAc)₂をこの混合物に添加し、そして再度、窒素でスパージした(5分間)。この混合物を80℃で、撹拌しながら週末をまたいで加熱した。この反応物を室温まで冷却し、濾過して固体を除去し、EtOAcですすいだ。次いで、その濾液を、EtOAc(250mL)および重炭酸ナトリウム溶液(飽和,200mL)を含む分液漏斗に移した。その水層をEtOAcで２回抽出し、そして合わせた有機物をブラインで洗浄し、そしてMgSO₄で乾燥させた。この混合物を濃縮し、そしてシリカゲルクロマトグラフィー(0〜10% DCM/MeOH)により精製して、所望の生成物を黄褐色物質として得た(1.6g,収率75%)。

In a round bottom flask, tert-butyl 2-methyl-4- (p-tolylsulfonyloxy) -7,8-dihydro-5H-pyrido [4,3-d] pyrimidine-6-carboxylate (2.73 g, 6.51 mmol) was added along with the appropriate boronic acid (3.0 eq), K ₃ PO ₄ (6.0 eq), and 2-dicyclohexylphosphino-biphenyl (0.1 eq) followed by sparging with nitrogen (10 min). . To this mixture was added dioxane (100 mL) and H ₂ O (1.0 mL). Again, the mixture was sparged with nitrogen (5 minutes). Pd (OAc) ₂ was added to the mixture and again sparged with nitrogen (5 minutes). The mixture was heated at 80 ° C. over the weekend with stirring. The reaction was cooled to room temperature and filtered to remove solids and rinsed with EtOAc. The filtrate was then transferred to a separatory funnel containing EtOAc (250 mL) and sodium bicarbonate solution (saturated, 200 mL). The aqueous layer was extracted twice with EtOAc and the combined organics were washed with brine and dried over MgSO ₄ . The mixture was concentrated and purified by silica gel chromatography (0-10% DCM / MeOH) to give the desired product as a tan material (1.6 g, 75% yield).

適切なアルデヒドまたはケトンをDCMに溶解させた。この混合物に、チタンテトライソプロポキシド(2.6当量)および適切なアミン(1.5当量)を添加した。この混合物を室温で一晩撹拌した。完全な還元がLCMSにより見られるまで、この混合物に、メタノール(DCMに対して1体積当量)およびNaBH₄(1.5当量)を、室温で撹拌しながら添加した。２滴のNaOH(2N)を添加し、そして得られた混合物をセライトで濾過し、そしてDCMですすいだ。得られた濾液をSiO₂上で濃縮し、そして0〜20% DCM/MeOH、および必要であれば、逆相C₁₈HPLCで精製した。

The appropriate aldehyde or ketone was dissolved in DCM. To this mixture was added titanium tetraisopropoxide (2.6 eq) and the appropriate amine (1.5 eq). The mixture was stirred at room temperature overnight. To this mixture was added methanol (1 volume equivalent to DCM) and NaBH ₄ (1.5 equivalent) with stirring at room temperature until complete reduction was seen by LCMS. Two drops of NaOH (2N) were added and the resulting mixture was filtered through celite and rinsed with DCM. The resulting filtrate was concentrated on SiO ₂ and purified by 0-20% DCM / MeOH and, if necessary, reverse phase C ₁₈ HPLC.

丸底フラスコ中で、N-アセテート基を含む適切な化合物を、MeOHに添加した。10NのNaOH(25〜50当量)をこの混合物に添加し、そして加熱還流した。完全な脱保護が起こるまで、この反応をLCMSにより監視した。完了したら、この反応物を冷却し、そしてHClで中和し、そしてこの溶液を分液漏斗に移し、そしてDCM(3回)で抽出した。合わせた有機物をMgSO₄で乾燥させ、そしてSiO₂上で濃縮した。この粗製混合物をシリカゲルクロマトグラフィー0〜20% DCM/MeOHにより精製して、所望の脱保護アミンを得た。

In a round bottom flask, the appropriate compound containing an N-acetate group was added to MeOH. 10N NaOH (25-50 eq) was added to the mixture and heated to reflux. The reaction was monitored by LCMS until complete deprotection occurred. When complete, the reaction was cooled and neutralized with HCl, and the solution was transferred to a separatory funnel and extracted with DCM (3 times). The combined organics were dried over MgSO ₄ and concentrated over SiO ₂ . The crude mixture was purified by silica gel chromatography 0-20% DCM / MeOH to give the desired deprotected amine.

適切なスルホンアミドをDMFに溶解させ、そして0℃に冷却した。この溶液に水素化ナトリウム(3.2当量)を添加し、そしてこの反応物を30分間撹拌した。2-メトキシエトキシメチルクロリド(MEMCl)(3.0当量)をこの溶液にゆっくりと添加し、そしてLCMSにより完了が判断されるまで、この反応物を室温で撹拌した。この混合物を減圧下で濃縮し、そしてその残渣をEtOAcに溶解させた。その有機物をH₂O(3回)およびブライン(1回)で洗浄し、Na₂SO₄で乾燥させ、そしてSiO₂上で濃縮した。この混合物をシリカゲルクロマトグラフィー(0〜100% EtOAc/ヘキサン)により精製した。

The appropriate sulfonamide was dissolved in DMF and cooled to 0 ° C. To this solution was added sodium hydride (3.2 eq) and the reaction was stirred for 30 minutes. 2-Methoxyethoxymethyl chloride (MEMCl) (3.0 eq) was slowly added to the solution and the reaction was stirred at room temperature until judged complete by LCMS. The mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc. The organics were washed with H ₂ O (3 times) and brine (1 time), dried over Na ₂ SO ₄ and concentrated over SiO ₂ . The mixture was purified by silica gel chromatography (0-100% EtOAc / hexanes).

適切なMEM保護化合物をEtOHに溶解させた。HCl/ジオキサンの溶液(4M,10〜25当量)を添加し、そしてLCMSにより判断して完全な脱保護まで、この混合物を還流した。この混合物を濃縮してそのまま使用したか、あるいはこの混合物をDCMを含む分液漏斗に移し、そしてその有機物をNaHCO₃の飽和溶液(1回)、H₂O(1回)、ブライン(1回)で洗浄し、そしてMgSO₄で乾燥させた。合わせた有機物を濃縮し、そしてシリカゲルクロマトグラフィー(0〜20% DCM/MeOH)により精製した。

Appropriate MEM protection compounds were dissolved in EtOH. A solution of HCl / dioxane (4M, 10-25 eq) was added and the mixture was refluxed until complete deprotection as judged by LCMS. The mixture was concentrated and used as such, or the mixture was transferred to a separatory funnel containing DCM and the organics were washed with a saturated solution of NaHCO ₃ (1 ×), H ₂ O (1 ×), brine (1 × ) And dried over MgSO ₄ . The combined organics were concentrated and purified by silica gel chromatography (0-20% DCM / MeOH).

適切なハロゲン化アリール(1.0当量)、4-エチニルアニリン(1.0当量)、Pd(PPh₃)₄(0.1当量)およびCuI(0.05当量)をDMFに溶解させた。得られた混合物を窒素でスパージし、そしてEt₃N(1.5当量)を添加した。この混合物を80℃で一晩加熱した。進行をLCMSにより監視し、そして完了したら、この反応物をSiO₂上で濃縮し、そしてシリカゲルクロマトグラフィー(0〜50% EtOAc/ヘキサン)により精製した。

Appropriate aryl halide (1.0 eq), 4-ethynylaniline (1.0 eq), Pd (PPh ₃ ) ₄ (0.1 eq) and CuI (0.05 eq) were dissolved in DMF. The resulting mixture was sparged with nitrogen and Et ₃ N (1.5 eq) was added. The mixture was heated at 80 ° C. overnight. Progress was monitored by LCMS and when complete, the reaction was concentrated on SiO ₂ and purified by silica gel chromatography (0-50% EtOAc / hexanes).

適切なBOC保護アミン(1.0当量)のCH₂Cl₂中の溶液(0.2M)に、HCl/ジオキサン(3.0当量)を滴下により添加した。この混合物を室温で一晩撹拌し、濃縮し、そしてその残渣をシリカゲルクロマトグラフィーにより精製した。

To a solution (0.2 M) of the appropriate BOC protected amine (1.0 eq) in CH ₂ Cl ₂ was added HCl / dioxane (3.0 eq) dropwise. The mixture was stirred at room temperature overnight, concentrated and the residue was purified by silica gel chromatography.

適切なアミン(2.95mmol)および2,6-ルチジン(3.25mmol)のDMF(0.2M)中の溶液に、ヨウ化メチル(1当量)を添加した。LCMSにより完了するまで、この混合物を撹拌した。この反応混合物を濃縮し、そしてそのまま使用した。

To a solution of the appropriate amine (2.95 mmol) and 2,6-lutidine (3.25 mmol) in DMF (0.2 M) was added methyl iodide (1 eq). The mixture was stirred until complete by LCMS. The reaction mixture was concentrated and used as such.

適切なアルコール(1.0当量)のCH₂Cl₂中の溶液に、トリエチルアミン(1.5当量)およびトリメチルシリルクロリド(TMSCl)(1.1当量)を添加した。この混合物を室温で一晩撹拌した。薄層クロマトグラフィーにより判断される場合にこの反応が完了しない場合、TMSCl(1.5当量)を添加し、そしてTLCにより完了が判断されるまでこの混合物を撹拌した。この混合物を濃縮し、そしてカラムクロマトグラフィーにより精製した。

To a solution of the appropriate alcohol (1.0 eq) in CH ₂ Cl ₂ was added triethylamine (1.5 eq) and trimethylsilyl chloride (TMSCl) (1.1 eq). The mixture was stirred at room temperature overnight. If the reaction was not complete as judged by thin layer chromatography, TMSCl (1.5 eq) was added and the mixture was stirred until judged complete by TLC. The mixture was concentrated and purified by column chromatography.

適切なアルコール(0.40mmol)をTHF(2.0mL)に溶解させ、そして-78℃に冷却した。この冷溶液にNaH(1.2mmol)を添加した。さらなる気体の発生が見えなくなるまで、この反応混合物を撹拌した。適切な臭化物(1.1当量)を添加し、次いでアセトン/ドライアイ浴を除きそしてこの混合物を一晩、室温まで温めた。この混合物を濃縮し、そしてシリカゲルカラムクロマトグラフィーにより精製した。

The appropriate alcohol (0.40 mmol) was dissolved in THF (2.0 mL) and cooled to -78 ° C. To this cold solution was added NaH (1.2 mmol). The reaction mixture was stirred until no further gas evolution was visible. Appropriate bromide (1.1 eq) was added, then the acetone / dry eye bath was removed and the mixture was allowed to warm to room temperature overnight. The mixture was concentrated and purified by silica gel column chromatography.

適切なニトロ含有化合物(1.0当量)を、アセトニトリルと酢酸(6.0当量)との溶液(0.2M)に溶解させた。この混合物に豊富な量の鉄粉(>5当量)を添加した。TLCにより完了するまでおよそ一晩、この反応混合物を還流した。次いで、この反応混合物をセライトで濾過し、濃縮し、そしてシリカゲルカラムクロマトグラフィーにより精製した。

The appropriate nitro-containing compound (1.0 eq) was dissolved in a solution of acetonitrile and acetic acid (6.0 eq) (0.2 M). A rich amount of iron powder (> 5 eq) was added to the mixture. The reaction mixture was refluxed approximately overnight until complete by TLC. The reaction mixture was then filtered through celite, concentrated and purified by silica gel column chromatography.

適切なカルボン酸(1.0当量)をCH₂Cl₂(0.2M)に溶解させ、そして0℃に冷却した。塩化オキサリル(1.1当量)を滴下により添加し、続いて数滴のDMFを添加した。この溶液を室温まで温め、濃縮し、そしてその残渣をDCE(0.2M)に溶解させた。この溶液に適切なアミン/アニリン(1.1当量)および触媒量のDMAPを添加した。この混合物を一晩還流し、濃縮し、そしてシリカゲルカラムクロマトグラフィーにより精製した。

The appropriate carboxylic acid (1.0 equiv) was dissolved in CH ₂ Cl ₂ (0.2M) and cooled to 0 ° C. Oxalyl chloride (1.1 eq) was added dropwise, followed by a few drops of DMF. The solution was warmed to room temperature, concentrated, and the residue was dissolved in DCE (0.2M). To this solution was added the appropriate amine / aniline (1.1 equiv) and a catalytic amount of DMAP. The mixture was refluxed overnight, concentrated and purified by silica gel column chromatography.

塩化トシル(TsCl)(2.1g,11.00mmol)を、N-ヒドロキシアセトイミド酸エチル(1.2g,11.6mmol)およびトリエチルアミン(8.88mL,63.7mmol)のDMF(20mL)中の溶液に、0℃で添加した。この反応混合物を1時間、室温まで温めた。この混合物を氷水(100mL)に注ぎ、そして撹拌した。黄色固体を濾別し、冷水(3×50mL)で洗浄した。その濾過した固体を60%のHClO₄で1時間処理し、そして室温まで冷却した。水をこの反応混合物に添加し(100mL)、そしてCH₂Cl₂(50mL)で抽出しそして水(50mL)で洗浄した。その生成物のCH₂Cl₂中の得られた溶液をそのまま使用した。

Tosyl chloride (TsCl) (2.1 g, 11.00 mmol) was added to a solution of ethyl N-hydroxyacetimidate (1.2 g, 11.6 mmol) and triethylamine (8.88 mL, 63.7 mmol) in DMF (20 mL) at 0 ° C. Added. The reaction mixture was warmed to room temperature for 1 hour. The mixture was poured into ice water (100 mL) and stirred. The yellow solid was filtered off and washed with cold water (3 × 50 mL). The filtered solid was treated with 60% HClO ₄ for 1 hour and cooled to room temperature. Water was added to the reaction mixture (100 mL) and extracted with CH ₂ Cl ₂ (50 mL) and washed with water (50 mL). The resulting solution of the product in CH ₂ Cl ₂ was used as is.

5mLのCH₂Cl₂中H₂NOTsの溶液を、1mLのCH₂Cl₂に溶解させた適切なピリジル化合物(488mmol)に添加し、そして室温で3時間撹拌した。この混合物を濃縮し、そしてその残渣をMeOHに溶解させ、そしてセライト上でエバポレートした。この混合物を逆相カラムクロマトグラフィーにより精製した。

A solution of H ₂ NOTs in 5 mL CH ₂ Cl ₂ was added to the appropriate pyridyl compound (488 mmol) dissolved in 1 mL CH ₂ Cl ₂ and stirred for 3 h at room temperature. The mixture was concentrated and the residue was dissolved in MeOH and evaporated on celite. The mixture was purified by reverse phase column chromatography.

トリエチルアミン(2当量)を適切なアミンのダイグライム(約0.2M)中の撹拌溶液に添加した。適切な塩化スルホニル(1.2当量)を添加し、そしてこの混合物を周囲温度で一晩撹拌した。ほとんどのダイグライムを減圧中で除去した。その残渣をH₂Oに溶解させ、そして酢酸エチルで数回抽出した。合わせた有機画分を水、ブラインで洗浄し、そしてNa₂SO₄で乾燥させた。そのスルホンアミド生成物をシリカゲルクロマトグラフィーにより精製した。

Triethylamine (2 eq) was added to a stirred solution of the appropriate amine in diglyme (ca. 0.2 M). Appropriate sulfonyl chloride (1.2 eq) was added and the mixture was stirred overnight at ambient temperature. Most diglyme was removed in vacuo. The residue was dissolved in H ₂ O and extracted several times with ethyl acetate. The combined organic fractions were washed with water, brine and dried over Na ₂ SO ₄ . The sulfonamide product was purified by silica gel chromatography.

トリエチルアミン(2当量)を適切なアニリンのダイグライム中の撹拌溶液(約0.2M)に添加した。所望の酸塩化物(1.2当量)を添加し、そしてこの混合物を周囲温度で一晩撹拌した。ほとんどのダイグライムを減圧中で除去した。その残渣をH₂Oに溶解させ、そして酢酸エチルで数回抽出した。合わせた有機画分を水、ブラインで洗浄し、そしてNa₂SO₄で乾燥させた。そのアミド生成物をシリカゲルクロマトグラフィーで精製した。

Triethylamine (2 eq) was added to a stirred solution of aniline in appropriate diglyme (ca. 0.2 M). The desired acid chloride (1.2 eq) was added and the mixture was stirred overnight at ambient temperature. Most diglyme was removed in vacuo. The residue was dissolved in H ₂ O and extracted several times with ethyl acetate. The combined organic fractions were washed with water, brine and dried over Na ₂ SO ₄ . The amide product was purified by silica gel chromatography.

適切なアミン(0.2M)の水溶液を3Mの水性NaOH(3当量)で処理した。10分間撹拌した後に、ジ炭酸ジ-tert-ブチル(Boc₂O)(1.2当量)を添加した。この混合物を周囲温度で一晩撹拌した。この溶液を3M水性HClでゆっくりとpH3に酸性化した。得られた白色沈殿物を減圧濾過により集め、H₂Oで洗浄し、凍結させ、そして凍結乾燥により乾燥させた。この物質をさらに精製せずに使用した。

An aqueous solution of the appropriate amine (0.2M) was treated with 3M aqueous NaOH (3eq). After stirring for 10 minutes, di-tert-butyl dicarbonate (Boc ₂ O) (1.2 eq) was added. The mixture was stirred overnight at ambient temperature. The solution was slowly acidified to pH 3 with 3M aqueous HCl. The resulting white precipitate was collected by vacuum filtration, washed with H ₂ O, frozen and dried by lyophilization. This material was used without further purification.

適切なアミン(1当量)のDMF(0.1M)中の溶液をK₂CO₃(5当量)で処理し、そして30分間撹拌した。適切な臭化ベンジルを添加し、そしてこの反応物を周囲温度で一晩撹拌した。ほとんどのDMFを減圧中で除去した。その残渣をDCMに溶解させ、そしてH₂Oで数回洗浄した。その有機層を無水Na₂SO₄(s)で乾燥させた。その粗製物質をシリカゲルクロマトグラフィーにより精製した。

A solution of the appropriate amine (1 eq) in DMF (0.1 M) was treated with K ₂ CO ₃ (5 eq) and stirred for 30 min. Appropriate benzyl bromide was added and the reaction was stirred overnight at ambient temperature. Most of the DMF was removed in vacuo. The residue was dissolved in DCM and washed several times with H ₂ O. The organic layer was dried over anhydrous Na ₂ SO ₄ (s). The crude material was purified by silica gel chromatography.

適切なFmoc保護アミンのDMF(0.26M)中の溶液を、2.4当量のピペリジンで処理し、そして周囲温度で一晩撹拌した。ほとんどのDMFを減圧中で除去し、そしてその残渣をH₂Oに溶解させ、そしてEtOAcで数回洗浄した。合わせた有機画分をH₂Oで逆抽出した。その水を減圧中で除去し、そして所望の化合物をそのまま使用した。

A solution of the appropriate Fmoc protected amine in DMF (0.26M) was treated with 2.4 equivalents of piperidine and stirred overnight at ambient temperature. Most of the DMF was removed in vacuo and the residue was dissolved in H ₂ O and washed several times with EtOAc. The combined organic fractions were back extracted with H ₂ O. The water was removed in vacuo and the desired compound was used as is.

m-CPBA(2.2当量)をDCM(0.2M)中の所望のピリジル化合物に添加した。得られた混合物を室温で1〜2時間撹拌した。この混合物を濃縮し、そしてシリカゲルクロマトグラフィーにより精製した。

m-CPBA (2.2 eq) was added to the desired pyridyl compound in DCM (0.2M). The resulting mixture was stirred at room temperature for 1-2 hours. The mixture was concentrated and purified by silica gel chromatography.

tert-ブチルジフェニルシリルクロリド(TBDPSCl)(1.2当量)をCH₂Cl₂(0.2M)中の適切なビスフェノール(1当量)およびEt₃N(1.5当量)に添加し、そしてこの溶液を室温で2.5時間撹拌した。この混合物をH₂Oで洗浄し、Na₂SO₄で乾燥させ、そして濃縮した。適切な臭化物(1当量)、K₂CO₃(3当量)、およびDMF(0.5M)を添加し、そしてこの溶液を90℃で一晩加熱した。17時間後、EtOAcを添加し、そしてこの溶液を10%のHCl、H₂O、およびブラインで洗浄し、Na₂SO₄で乾燥させ、そして濃縮した。得られた油状物をシリカゲルクロマトグラフィーにより精製した。

tert-Butyldiphenylsilyl chloride (TBDPSCl) (1.2 eq) was added to the appropriate bisphenol (1 eq) and Et ₃ N (1.5 eq) in CH ₂ Cl ₂ (0.2 M) and the solution was added at room temperature for 2.5 Stir for hours. The mixture was washed with H ₂ O, dried over Na ₂ SO ₄ and concentrated. Appropriate bromide (1 eq), K ₂ CO ₃ (3 eq), and DMF (0.5 M) were added and the solution was heated at 90 ° C. overnight. After 17 hours, EtOAc was added and the solution was washed with 10% HCl, H ₂ O, and brine, dried over Na ₂ SO ₄ and concentrated. The resulting oil was purified by silica gel chromatography.

MeOHおよびNaBH₄(1.2当量)を適切なケトンまたはアルデヒドに添加し、そしてこの反応物を室温で3時間撹拌した。この反応混合物を濃縮し、そしてシリカゲルクロマトグラフィーにより精製した。

MeOH and NaBH ₄ (1.2 eq) were added to the appropriate ketone or aldehyde and the reaction was stirred at room temperature for 3 hours. The reaction mixture was concentrated and purified by silica gel chromatography.

適切なハロゲン化アルキル(3当量)をTHF中の適切なアミンおよびEt₃N(3当量)に添加した。この溶液を一晩加熱還流した。この溶液を濃縮し、そしてシリカゲルクロマトグラフィーにより精製した。

Appropriate alkyl halide (3 eq) was added to the appropriate amine and Et ₃ N (3 eq) in THF. The solution was heated to reflux overnight. The solution was concentrated and purified by silica gel chromatography.

塩化チオニル(2当量)をMeOH中の適切な酸に滴下により添加した。得られた溶液を2〜4時間加熱還流し、そして濃縮した。その生成物をさらに精製せずに持ち越した。

Thionyl chloride (2 eq) was added dropwise to the appropriate acid in MeOH. The resulting solution was heated to reflux for 2-4 hours and concentrated. The product was carried forward without further purification.

LiAlH₄(1.2当量,THF中2M)をTHF中の適切なエステル(1当量)にゆっくりと添加し、そしてこの溶液を室温で一晩撹拌する。水、10%のNaOH、およびさらなる水を滴下により添加し、そして得られたスラリーをセライトで濾過し、大過剰の酢酸エチルで洗浄した。その有機物をNa₂SO₄で乾燥させ、そして濃縮して、所望の生成物を得た。

LiAlH ₄ (1.2 eq, 2M in THF) is slowly added to the appropriate ester (1 eq) in THF and the solution is stirred at room temperature overnight. Water, 10% NaOH, and additional water were added dropwise, and the resulting slurry was filtered through celite and washed with a large excess of ethyl acetate. The organics were dried over Na ₂ SO ₄ and concentrated to give the desired product.

BuLi(1.2当量,ヘキサン中2.5M)を、THF中の適切なホスフェートに-78℃でゆっくりと添加した。この混合物を-78℃で15分間撹拌し、適切なアルデヒド(1.2当量)を添加し、そしてこの溶液を一晩で室温に温めた。この反応混合物を濃縮し、そしてシリカゲルクロマトグラフィーにより精製した。

BuLi (1.2 eq, 2.5M in hexane) was slowly added to the appropriate phosphate in THF at -78 ° C. The mixture was stirred at −78 ° C. for 15 minutes, the appropriate aldehyde (1.2 eq) was added, and the solution was allowed to warm to room temperature overnight. The reaction mixture was concentrated and purified by silica gel chromatography.

適切な臭化アリール(1当量)、適切なイミダゾール(1.2当量)、CuI(0.2当量)、8-ヒドロキシキノリン(0.2当量)、およびK₂CO₃をDMSO(ArBrあた1M)に懸濁させ、そしてN₂で1〜5分間パージした。この溶液を120℃で16〜40時間加熱し、濾過し、そして逆相シリカゲルクロマトグラフィーにより精製した。

Suspend appropriate aryl bromide (1 eq), appropriate imidazole (1.2 eq), CuI (0.2 eq), 8-hydroxyquinoline (0.2 eq), and K ₂ CO ₃ in DMSO (ArBr + 1 M). And purged with N ₂ for 1-5 min. The solution was heated at 120 ° C. for 16-40 hours, filtered and purified by reverse phase silica gel chromatography.

DMF(0.5M)中の適切なアルコール(1当量)をNaH(1.2当量,鉱油中60% w/w)で処理し、そして室温で20〜30分間撹拌した。4-フルオロ-1-ニトロベンゼン(1.2当量)を添加し、そしてこの溶液を室温〜60℃で3-24時間撹拌した。この反応混合物をEtOAcで希釈し、10%のHCl、水、ブラインで洗浄し、Na₂SO₄で乾燥させ、そしてシリカゲルクロマトグラフィーにより精製した。

The appropriate alcohol (1 eq) in DMF (0.5 M) was treated with NaH (1.2 eq, 60% w / w in mineral oil) and stirred at room temperature for 20-30 min. 4-Fluoro-1-nitrobenzene (1.2 eq) was added and the solution was stirred at room temperature to 60 ° C. for 3-24 hours. The reaction mixture was diluted with EtOAc, washed with 10% HCl, water, brine, dried over Na ₂ SO ₄ and purified by silica gel chromatography.

適切なアミン(1当量)をDMF中の適切なイソシアネート(1当量)に0℃で添加し、そしてこの溶液を0℃で90分間撹拌した。適切なアミン(1.2当量)および2,6-ルチジン(1.2当量)を添加し、そしてこの溶液を60℃で一晩撹拌し、濃縮し、そしてシリカゲルクロマトグラフィーにより精製した。

Appropriate amine (1 eq) was added to the appropriate isocyanate (1 eq) in DMF at 0 ° C. and the solution was stirred at 0 ° C. for 90 min. Appropriate amine (1.2 eq) and 2,6-lutidine (1.2 eq) were added and the solution was stirred at 60 ° C. overnight, concentrated and purified by silica gel chromatography.

適切な臭化ベンジル(1当量)をDMF中の適切なアミン(1当量)に添加した。そしてこの溶液を80℃で一晩撹拌した。この混合物をEtOAcで希釈し、飽和NaHCO₃で洗浄し、Na₂SO₄で乾燥させ、そして濃縮した。この生成物を粗製のまま持ち越した。

Appropriate benzyl bromide (1 eq) was added to the appropriate amine (1 eq) in DMF. The solution was then stirred at 80 ° C. overnight. The mixture was diluted with EtOAc, washed with saturated NaHCO ₃ , dried over Na ₂ SO ₄ and concentrated. This product was carried over crude.

MeI(1.5当量)をDMF中の適切なカルボン酸(1当量)およびK₂CO₃(3当量)に添加した。この溶液を60℃で3時間撹拌した。EtOAcを添加し、そして10%のHCl、水、ブラインで洗浄し、Na₂SO₄で乾燥させ、濾過し、そして濃縮した。THFおよびPhCH₃を添加し、LiBH₄(0.7当量,THF中2M)をゆっくりと添加し、そしてこの混合物を100℃で4時間、次いで室温で加熱した。4時間後、LiBH₄(0.7当量,THF中2M)を添加した。23時間後、LiBH₄(0.7当量,THF中2M)を添加し、そしてこの溶液を100℃に加熱した。100℃で6時間後、この溶液を冷却し、水およびEtOACで希釈し、そして室温で1時間撹拌した。その層を分離し、その有機層をNa₂SO₄で乾燥させ、濃縮し、そしてシリカゲルクロマトグラフィーにより精製した。

MeI (1.5 eq) was added to the appropriate carboxylic acid (1 eq) and K ₂ CO ₃ (3 eq) in DMF. The solution was stirred at 60 ° C. for 3 hours. EtOAc was added and washed with 10% HCl, water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. THF and PhCH ₃ were added, LiBH ₄ (0.7 eq, 2M in THF) was added slowly, and the mixture was heated at 100 ° C. for 4 hours and then at room temperature. After 4 hours, LiBH ₄ (0.7 eq, 2M in THF) was added. After 23 hours, LiBH ₄ (0.7 eq, 2M in THF) was added and the solution was heated to 100 ° C. After 6 hours at 100 ° C., the solution was cooled, diluted with water and EtOAC and stirred at room temperature for 1 hour. The layers were separated and the organic layer was dried over Na ₂ SO ₄ , concentrated and purified by silica gel chromatography.

クロロオキソ酢酸メチル(1.2当量)をDCM中の適切なアミン(1当量)およびEt₃N(3当量)に添加し、そしてこの溶液を室温で1時間撹拌した。この溶液をDCMで希釈し、10%のHClで洗浄し、Na₂SO₄で乾燥させ、そして濃縮した。過剰なNaOH/H₂OおよびMeOHを添加し、そしてこの混合物を1時間加熱還流し、この混合物をEtOAcで希釈し、10%のHClで洗浄し、Na₂SO₄で乾燥させ、そして濃縮した。DCMおよび塩化オキサリル(2当量)を添加し、続いて1滴のDMFを添加した。この溶液を室温で30分間撹拌し、そして濃縮した。DCM、続いてEt₃N(3当量)および適切なアミン(1当量)を添加し、そしてこの溶液を室温で1時間撹拌した。この溶液をDCMで希釈し、10%のHClで洗浄し、Na₂SO₄で乾燥させ、そして濃縮した。得られた物質を粗製のまま持ち越した。

Methyl chlorooxoacetate (1.2 eq) was added to the appropriate amine (1 eq) and Et ₃ N (3 eq) in DCM and the solution was stirred at room temperature for 1 h. The solution was diluted with DCM, washed with 10% HCl, dried over Na ₂ SO ₄ and concentrated. Excess NaOH / H ₂ O and MeOH were added and the mixture was heated to reflux for 1 h, the mixture was diluted with EtOAc, washed with 10% HCl, dried over Na ₂ SO ₄ and concentrated. . DCM and oxalyl chloride (2 eq) were added followed by 1 drop of DMF. The solution was stirred at room temperature for 30 minutes and concentrated. DCM was added followed by Et ₃ N (3 eq) and the appropriate amine (1 eq) and the solution was stirred at room temperature for 1 h. The solution was diluted with DCM, washed with 10% HCl, dried over Na ₂ SO ₄ and concentrated. The resulting material was carried over crude.

適切な塩化スルホニル(1当量)をピリジン(0.8M)中のヒドロキシルアミン塩酸塩(2当量)にゆっくりと添加した。この溶液を室温で1時間撹拌し、10%のHClに注ぎ、そして冷凍庫内で一晩冷却した。得られた溶液を濾過し、10%のHClに懸濁させ、そして4時間加熱還流した。この溶液を1MのNaOHで中和し、EtOAcで洗浄し、そしてその有機層をNa₂SO₄で乾燥させ、そして濃縮した。得られた物質を粗製のまま持ち越した。

Appropriate sulfonyl chloride (1 eq) was slowly added to hydroxylamine hydrochloride (2 eq) in pyridine (0.8 M). The solution was stirred at room temperature for 1 hour, poured into 10% HCl and cooled in the freezer overnight. The resulting solution was filtered, suspended in 10% HCl and heated to reflux for 4 hours. The solution was neutralized with 1M NaOH, washed with EtOAc, and the organic layer was dried over Na ₂ SO ₄ and concentrated. The resulting material was carried over crude.

メタンスルホニルクロリド(1.1当量)を、適切な保護アミノアルコール(1.0当量)およびトリエチルアミンのCH₂Cl₂中の溶液に0℃で添加した。この反応混合物を室温まで温めた。そして一晩撹拌した。この混合物をセライトで濾過し、そしてその濾液を濃縮した。このように得られたメシレートをDMFに溶解させ、NaN₃(4.0当量)を添加し、そして得られた混合物を85℃で一晩撹拌した。室温まで冷却した後に、この反応混合物を水とEtOAcとの間で分配し、その層を分離し、そしてその水層をEtOAcで抽出した(2回)。合わせた有機抽出物を水(1回)、ブライン(1回)で洗浄し、乾燥させ(Na₂SO₄)、濾過し、そして濃縮した。このように得られたアジドを引き続く反応においてそのまま使用した。

Methanesulfonyl chloride (1.1 eq) was added to a solution of the appropriate protected aminoalcohol (1.0 eq) and triethylamine in CH ₂ Cl ₂ at 0 ° C. The reaction mixture was warmed to room temperature. And stirred overnight. The mixture was filtered through celite and the filtrate was concentrated. The mesylate thus obtained was dissolved in DMF, NaN ₃ (4.0 eq) was added and the resulting mixture was stirred at 85 ° C. overnight. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc, the layers were separated, and the aqueous layer was extracted with EtOAc (twice). The combined organic extracts were washed with water (1 ×), brine (1 ×), dried (Na ₂ SO ₄ ), filtered and concentrated. The azide thus obtained was used as such in the subsequent reaction.

CuSO₄・5H₂O(0.01当量)を、適切なアルキルアジド(1.0当量)、適切なアルキン(1.0当量)、およびアスコルビン酸ナトリウム(0.1当量)の水/t-ブタノール(1mL:1mL)中の懸濁物に添加し、そして得られた混合物を50℃で一晩撹拌した。この反応混合物を室温まで冷却し、その溶媒を除去し、そして得られた残渣をクロマトグラフィーにより精製して、所望の生成物を得た。

CuSO a ₄ · 5H ₂ O (0.01 equiv), the appropriate alkyl azide (1.0 eq), the appropriate alkyne (1.0 eq), and sodium ascorbate (0.1 equivalent) of water / t-butanol (1 mL: 1 mL) solution of The suspension was added and the resulting mixture was stirred at 50 ° C. overnight. The reaction mixture was cooled to room temperature, the solvent was removed, and the resulting residue was purified by chromatography to give the desired product.

塩化オキサリル(1.8当量)を、適切な酸(1.3当量)のCH₂Cl₂中の混合物に0℃で添加し、続いてDMF(2〜3滴)を添加した。次いで、この混合物を室温で1時間撹拌した。その溶媒を減圧下で除去し、そして得られた残渣をCH₂Cl₂に溶解させた。この混合物に、適切なアニリン(1.0当量)、Et₃N(1.5当量)、およびDMAP(触媒量)のCH₂Cl₂中の溶液を添加し、そして得られた混合物を室温で一晩撹拌した。この反応混合物を濃縮し、そしてクロマトグラフィーにより精製した。

Oxalyl chloride (1.8 eq) was added to a mixture of the appropriate acid (1.3 eq) in CH ₂ Cl ₂ at 0 ° C., followed by DMF (2-3 drops). The mixture was then stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the resulting residue was dissolved in CH ₂ Cl ₂ . To this mixture was added a solution of the appropriate aniline (1.0 eq), Et ₃ N (1.5 eq), and DMAP (catalytic amount) in CH ₂ Cl ₂ and the resulting mixture was stirred at room temperature overnight. . The reaction mixture was concentrated and purified by chromatography.

適切なN-アセチルアニリン(1.0当量)の、2.0NのHCl/THF(約3mL/1mL)中の混合物を、還流しながら一晩撹拌した。この混合物を室温まで冷却し、そして固体沈殿物を濾過により集めた。そのフィルターケーキをEt₂Oで洗浄し、そして減圧下で乾燥させた。冷却しても沈殿物が形成されない場合、その溶媒を除去し、そして得られた残渣をEt₂O/EtOAcに懸濁させた。得られた沈殿物を濾過により集め、そして減圧下で乾燥させた。

A mixture of the appropriate N-acetylaniline (1.0 eq) in 2.0 N HCl / THF (ca. 3 mL / 1 mL) was stirred at reflux overnight. The mixture was cooled to room temperature and the solid precipitate was collected by filtration. The filter cake was washed with Et ₂ O and dried under reduced pressure. If no precipitate formed upon cooling, the solvent was removed and the resulting residue was suspended in Et ₂ O / EtOAc. The resulting precipitate was collected by filtration and dried under reduced pressure.

適切なアミン、N'-シアノ-N-(4-ピリジル)カルバムイミドチオ酸メチル、Et₃N、およびDMAP(触媒量)を、ピリジン中で一晩加熱還流した。この溶液を冷却し、そしてEt₂Oに添加した。得られた残渣を濾過またはデカンテーションにより単離し、そしてシリカゲルクロマトグラフィーまたはRP-HPLCにより精製した。

The appropriate amine, methyl N′-cyano-N- (4-pyridyl) carbamimidothioate, Et ₃ N, and DMAP (catalytic amount) were heated to reflux overnight in pyridine. The solution was cooled and added to Et ₂ O. The resulting residue was isolated by filtration or decantation and purified by silica gel chromatography or RP-HPLC.

ジクロロエタン(2mL)中の適切に保護されたピペラジン(0.074mmol)に、アセトン(0.74mmol)を添加した。5分間撹拌した後に、トリアセトキシ水素化ホウ素ナトリウム(0.15mmol)をこの混合物に添加した。この反応物を24時間撹拌し、次いでMeOH(5mL)の添加によりクエンチした。この反応物を濃縮し、そして逆相(RP)-HPLCにより精製した。

To the appropriately protected piperazine (0.074 mmol) in dichloroethane (2 mL) was added acetone (0.74 mmol). After stirring for 5 minutes, sodium triacetoxyborohydride (0.15 mmol) was added to the mixture. The reaction was stirred for 24 hours and then quenched by the addition of MeOH (5 mL). The reaction was concentrated and purified by reverse phase (RP) -HPLC.

ジメチルスルホキシド(1mL)中の適切に保護されたフルオロ-ピリジル中間体(0.072mmol)に、モルホリン(0.72mmol)を添加した。この反応物を100℃で加熱し、そして24時間撹拌した。この反応物を濃縮し、そして逆相(RP)-HPLCにより精製した。

To the appropriately protected fluoro-pyridyl intermediate (0.072 mmol) in dimethyl sulfoxide (1 mL) was added morpholine (0.72 mmol). The reaction was heated at 100 ° C. and stirred for 24 hours. The reaction was concentrated and purified by reverse phase (RP) -HPLC.

DMF(12mL)中の適切な臭化アリール(3.6mmol)に、ビス(ピナコラト)ジボロン(7.3mmol)、1,1'-ビス(ジフェニルホスフィノ)フェロセン-パラジウム(II)ジクロリド錯体(0.36mmol)および酢酸カリウムを添加した。この反応物を撹拌し、そして80℃で一晩加熱した。この反応物を濃縮し、そしてシリカゲルクロマトグラフィー(DCM中0〜15%のMeOH)により精製して、所望の化合物を得た。

To a suitable aryl bromide (3.6 mmol) in DMF (12 mL), bis (pinacolato) diboron (7.3 mmol), 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride complex (0.36 mmol) And potassium acetate was added. The reaction was stirred and heated at 80 ° C. overnight. The reaction was concentrated and purified by silica gel chromatography (0-15% MeOH in DCM) to give the desired compound.

DMF(1.5mL)中の適切なボロン酸エステル(0.2mmol)に、テトラキス(トリフェニル-ホスフィン)パラジウム(0.02mmol)、および5-ブロモ-2-フルオロピリジン(0.3mmol)を添加した。窒素をこの反応物に5分間吹き込み、そして炭酸ナトリウム(250μL,2M)を添加した。窒素を再度、この反応に吹き込んだ。次いで、この反応物を、90℃で一晩加熱しながら撹拌した。その溶媒を減圧下で除去し、そしてその残渣を水とDCMとの間で分配した。その有機層を乾燥させ(MgSO4)、濃縮し、そしてC18クロマトグラフィーにより精製して、所望の生成物を得た。

To the appropriate boronic ester (0.2 mmol) in DMF (1.5 mL) was added tetrakis (triphenyl-phosphine) palladium (0.02 mmol) and 5-bromo-2-fluoropyridine (0.3 mmol). Nitrogen was bubbled through the reaction for 5 minutes and sodium carbonate (250 μL, 2M) was added. Nitrogen was again blown into the reaction. The reaction was then stirred with heating at 90 ° C. overnight. The solvent was removed under reduced pressure and the residue was partitioned between water and DCM. The organic layer was dried (MgSO4), concentrated and purified by C18 chromatography to give the desired product.

  Exemplary compounds of the invention are shown in Tables 1-4. Tables 1 and 3 are divided into “A” and “B”. The table “A” shows the structure, name, and NMR data (if generated) for the specific example compounds. Compound names were generated using ACD Labs IUPAC naming software version 12.00 (Toronto, Ontario, Canada).

  The “B” table shows the molecular weights obtained using high resolution mass spectrometry (“HRMS”) and also lists the synthetic procedures used to make the specific example compounds. In some instances, the synthetic procedures listed are similar to those actually used, not the actual procedures used to make the specific example compounds. Each of the example compounds was synthesized using commercially available starting materials that are well known in the art.

  Example compounds

Biochemical and biological examples Cytotoxicity assays
HCT116 cells were seeded in 96 well plates (Greiner Bio-One, Monroe, NC) and allowed to settle overnight. Test compounds dissolved in dimethyl sulfoxide (DMSO) were added and drug incubation was allowed to proceed for 72 hours. If applicable, make a 1000-fold solution of nicotinic acid (NA; Sigma-Aldrich, St. Louis, MO) dissolved in water and add 1 × NA (10 μM final concentration) simultaneously with the test compound did. After 72 hours, 50 μL of CellTiter-Glo Luminescent Cell Viability Assay reagent (Promega Corporation, Madison, Wis.) Was added to the cells in 200 μL of cell culture medium. After a predetermined incubation time, luminescence was measured using a TopCount NXT plate reader (PerkinElmer, Waltham, Mass.).

The example compounds listed in Table 1 and Table 3 showed cytotoxicity against HCT116 cells with an IC ₅₀ of less than 100 nM. For example, Example Compound No. 152 shows an IC ₅₀ of about 55 nM, Example Compound No. 164 shows an IC ₅₀ of about 74 nM, Example Compound No. 210 shows an IC ₅₀ of about 39 nM, and Examples Compound no. 605 exhibited an IC ₅₀ of about 1.1 nM.

Some of the example compounds listed in Table 2 and Table 4 showed cytotoxicity against HCT116 cells with an IC ₅₀ of 100 nM or higher, or were not tested in cytotoxicity assays. For example, Example Compound No. 363 shows an IC ₅₀ of about 290 nM, Example Compound No. 580 shows an IC ₅₀ of about 100 nM, Example Compound No. 613 shows an IC ₅₀ of about 2.6 μM, Example Compound No. 634 showed an IC ₅₀ of about 5.0 μM, and Example Compound No. 641 showed an IC ₅₀ of about 3.2 μM.

Direct target affinity purification (DTAP)
Test compounds of interest with alkyl-amine linkers were synthesized to allow covalent attachment to epoxy-activated Sepharose 6B beads (GE Healthcare, Piscataway, NJ). Sepharose beads were swollen and washed with water for 30 minutes, followed by equilibration in coupling buffer (50% dimethylformamide, 50 mM Na ₂ CO ₃ ). The beads were pelleted by centrifugation (2000 xg for 15 seconds) and the supernatant removed by aspiration. These beads were resuspended using an equal volume of coupling buffer containing the test compound with linker. The compound concentration in this coupling reaction ranged from 0.01 mM to 1 mM. These coupling reactions were incubated at 34 ° C. for 18 hours on a rotating mixer. Ethanolamine was added during the last hour to 1M to quench the coupling reaction. Wash the beads thoroughly with binding buffer (1M NaCl, 50 mM Hepes [pH 7.4], 1% Triton X-100, 1 mM EDTA and 1 mM dithiothreitol) to remove residual coupling reagent. Removed and then stored at 4 ° C.

Cell proteins were lysed with lysis buffer (150 mM NaCl, 50 mM Hepes [pH 7.4], 1% Triton X-100, 1 mM EDTA and 2 mM dithiothreitol (1 × Halt ^™ protease and phosphatase inhibitor cocktail [Thermo Fisher Scientific, Rockford, IL)))). The lysate was centrifuged (20,000 × g for 20 minutes) to remove debris, diluted to a protein concentration of approximately 5 mg / mL, divided into aliquots, and stored at −80 ° C.

  For the DTAP reaction, cell lysates (approximately 0.5 mL per binding reaction) were thawed and the NaCl concentration was adjusted to 1M. The competitor compound (or DMSO control) dissolved in DMSO was then added to the lysate and incubated for 5 minutes on ice. These lysates were centrifuged at 20,000 × g for 10 minutes and the clarified supernatant was transferred to a tube containing 50 μl coupled beads. The binding reactions were incubated for 2 hours at 4 ° C. on a rotary mixer, after which the beads were pelleted by centrifugation and the supernatant removed by aspiration. Beads three times with 20 volumes of binding buffer, 20 volumes of wash buffer (150 mM NaCl, 50 mM Hepes [pH 7.4], 1% Tween 20, 1 mM EDTA, 2 mM dithiothreitol) And finally twice with 10 volumes of 150 mM NaCl, 50 mM Hepes [pH 7.4].

  During the last wash, an aliquot containing 10 μl beads was transferred to another tube and resuspended in 15 μl 2 × SDS / PAGE loading buffer (Invitrogen Corporation, Carlsbad, Calif.) For 5 minutes at 90 ° C. . Eluted proteins were redissolved by electrophoresis on NuPage 4-12% Bis-Tris Gel (Invitrogen Corporation, Carlsbad, Calif.) And visualized by staining with Ruby Red (Invitrogen Corporation, Carlsbad, Calif.). The remaining beads (40 μl) were further processed for analysis by mass spectrometry.

  This assay was used to confirm the selectivity of targeting a subset of compounds of the present invention.

Liquid Chromatography-Mass Spectrometry Bound proteins were digested by treating these beads with trypsin as follows. After the final wash, the beads were resuspended in an equal volume of trypsin digestion buffer (50 mM ammonium bicarbonate (pH 8.0), 5% acetonitrile, 1 mM calcium chloride). Samples were reduced with 5 mM DTT for 15 minutes at 65 ° C. and alkylated with 10 mM iodoacetamide for 30 minutes at 30 ° C. in the dark. Sequencing grade modified trypsin (Promega Corporation, Madison, Wis.) Was added and samples were digested at 37 ° C. for 1.5 hours.

For one-dimensional LC-MS / MS, 5 μl aliquots (about 1/10 of the sample) were transferred to the NanoLC-AS1 autosampler (Eksigent, Dublin, CA) and NanoLC-2D (Eksigent, Dublin, CA). It was loaded onto an OPTI-PAK C ₁₈ trap column (Optimize Technologies, Oregon City, OR) in 0.1% formic acid in% acetonitrile. Peptides were eluted from the trap and separated on a flame-stretched 10 cm × 75 μM ID fused silica capillary column (Polymicro Technologies, Phoenix, AZ) self-packed with Synergy Hydro C ₁₈ media (Phenomenex, Torrence, Calif.). The following gradient was used: 5-15% B (0.1% formic acid in acetonitrile) for 5 minutes, 15-40% B for 60 minutes, 40-60% B for 5 minutes, 80-80% B for 10 minutes and 5-5% B for 10 minutes. The eluted peptide was ionized directly into LTQ-Orbitrap (Thermo Fisher Scientific, Inc., Waltham, MA). A full scan from m / z 300 to 2000 was performed on Orbitrap with a resolution of 60,000. Five ions from the strongest were selected for MS2 in LTQ (Full FT-Big 5 IT). The standardized collision energy was 35%.

Peptides and proteins were identified by searching raw mass spectrometry data against a forward and reverse human RefSeq database. The Sequest algorithm was used with the following parameters: peptide mass tolerance = 10 ppm, fragment ion tolerance = 1.0 kD, two lost truncations allowed, differential modification of methionine oxidation (15.994915), one peptide 3 possible modifications and 57.0215 constant cysteine modifications. After filtration, Bioworks 3.0 software (Thermo Fisher Scientific, Inc., Waltham, Mass.) Was used to identify proteins with a protein likelihood greater than 10 ⁻³ . There was a failed discovery rate of less than 0.5%. Hierarchical clustering was performed using the Bigcat software package (McAfee, KJ et al. Mol. Cell. Proteomics. 5, 1497-1513 (2006)).

Nampt activity assay
5-phosphoribosyl-1-pyrophosphate (PRPP), ATP, NaM, NaMN, Triton X-100, UDP-glucose and diaphorase were purchased from Sigma-Aldrich, St. Louis, MO. DNAs encoding human NAMPT, NMN adenylyltransferase (NMNAT1) and UDP-glucose dehydrogenase (UGDH) are each inserted into a self-modified E. coli expression vector, and the expressed protein has an N-terminal 6 × His tag I did it. These His-tagged proteins were expressed in the BL21-AI E. Coli expression strain (Invitrogen Corporation, Carlsbad, Calif.) And subsequently induced at 30 ° C. with 0.2% L-arabinose and 0.5 mM IPTG. The protein was purified with Ni-NTA resin (Qiagen, Germantown, MD).

The assay for Nampt catalytic activity was performed based on a previously published conjugate enzyme fluorescence measurement technique. This technique uses NADH as the final analyte (Revollo, JR et al. Biol. Chem. 279, 50754-50763 (2004)). Significant improvement in assay sensitivity was achieved by switching from direct detection for NADH to a resazurin / diaphorase-based fluorometric detection system (Guilbault, GG, and Kramer, DNAnal. Chem. 37, 1219-1221 (1965 )). Standard inhibition analysis was performed in a 96-well microtiter plate with 50 mM Tris-HCl (pH 7.5), 1% DMSO (v / v), 0.01% Triton X-100 (v / v), 10 mM MgCl ₂ , 2 mM ATP, 3 μM NAM, 8 μM PRPP, 50 pM Nampt, and the following detection reagents (5 nM Nmnat, 200 nM Ugdh, 200 μM UDP-glucose, 0.02 U / mL diaphorase and 0.25 μM Of resazurin) in real-time mode. After incubating the samples for up to 3 hours at room temperature, fluorescence intensity quantification at excitation and emission wavelengths, 510 nm and 590 nm, respectively, was performed using a Gemini XS plate reader (Molecular Devices, Sunnyvale, Calif.). A counter assay intended to consider false positives (eg inhibitors of detection enzymes or fluorescence quenchers) ineligible was performed essentially as described above except that 1 μM NaMN was used instead of Nampt. . A catalytically inactive Nampt-D313A mutant enzyme preparation was used as a negative control for assay development.

All of the compounds in Tables 1A and 1B, 2, 3A and 3B, and 4 were tested using this assay. For example, Example Compound No. 152 shows an in vitro IC _{50 of} about 2.0 nM, Example Compound No. 164 shows an in vitro IC _{50 of} about 1.8 nM, and Example Compound No. 210 shows an in vitro IC _{50 of} about 6.3 nM. Example Compound No. 363 shows an in vitro IC _{50 of} about 3.4 nM, Example Compound No. 580 shows an in vitro IC _{50 of} about 0.8 nM, and Example Compound No. 605 shows an in vitro IC ₅₀ of about 2.4 nM. showed ₅₀ example compound No. 613 showed in vitro IC ₅₀ of approximately 11 nM, example compound No. 634 showed in vitro IC ₅₀ of about 520 nM, and example compound No. 641, in vitro IC of approximately 1.3μM ₅₀ was shown.

The NAD ⁺ Assay cells for measuring NAD ⁺ in cell lysates were measured by modification of an existing protocol (Lee, HI, et .Exp.Mol.Med.40,246-253 (2008)). MCF-10A cells stably transduced with the PIK3CA (H1047R) oncogene were seeded at a very high density (100% confluence) in 96 well plates and allowed to settle overnight. Test compounds dissolved in DMSO were added and drug incubation was allowed to proceed for 20-24 hours. Cells were washed with PBS and harvested by incubation in 25 μL 0.5 M perchloric acid (HClO ₄ ) followed by vigorous shaking at 4 ° C. for 15 minutes. The acidic cell lysate was neutralized by adding 8 μL of 2M KOH / 0.2MK ₂ HPO ₄ . The entire volume of lysate was transferred to a centrifuge plate and centrifuged at 3000 rpm in a tabletop centrifuge (4 ° C.) for 5 minutes to remove the precipitate. Lysates were assayed for both NAD ⁺ and ATP. For NAD ⁺ measurements, 10 μL of lysate from the centrifuged plate was added to 90 μL of reaction solution in a Costar 96 half-well plate (Corning, Corning, NY). The final concentration of this reaction mixture is 120 μM Tris-HCl (pH 7.5), 0.01% Triton X-100, 35 μM UDP-glucose, 50 nM UGDH, 0.5 μM resazurin, and 0.1 unit / mL diaphorase. there were. The reaction was allowed to proceed for 1 hour at room temperature, after which time fluorescence was read as above with a Gemini plate reader. For ATP measurement, 5 μL of clarified lysate was added to 195 μL of PBS. 50 μL of CellTiter-Glo reagent (Promega Corporation, Madison, Wis.) Was added and ATP was measured as described in the cytotoxicity assay.

PAR Assay An imaging-based cellular assay was developed to measure poly (ADP-ribose) polymerase (PARP) activity. MCF-10A cells stably transduced with the PIK3CA (H1047R) oncogene were seeded in 96-well plates and allowed to settle overnight. Test compounds dissolved in DMSO were added and drug incubation was allowed to proceed for 20-24 hours. Under these conditions, Nampt inhibitors showed no evidence of toxicity. The next morning, hydrogen peroxide was added to these cells to a final concentration of 500 μM. After 8 minutes of hydrogen peroxide treatment, cells were fixed in 100% -20 ° C methanol. After rehydration and washing with PBS, cells were incubated in blocking buffer (HBSS, 1% BSA, 0.1% Tween20), then anti-PAR mouse monoclonal antibody (Trevigen, Gaithersburg, MD; blocking buffer) Stain overnight with a 1: 2000 dilution in the solution). Cells were washed with PBS and combined with 1: 1000 anti-mouse-Alexa488 (Invitrogen Corporation, Carlsbad, Calif.), 5 μg / mL Hoechst 33342 (Invitrogen), and 0.1 μg / mL HCS CellMask deep red (Invitrogen) Incubated in Cells were washed with PBS and then stored in blocking buffer.

  Images were acquired on a Pathway 855 instrument (BD Biosciences, San Jose, Calif.) Using a 10 × objective. Use Attovision software (BD Biosciences, San Jose, CA) to segment nuclei with Hoechst signal and then average the PAR signal for each nucleus in the well to produce one value did. After subtracting background using samples that were not incubated with anti-PAR primary antibody, PAR intensity per well was graphed (Prism; GraphPad Software, Inc .; La Jolla, CA).

NA Rescue and Naprt1 Expression Assay Cell lines were treated with a fixed dose of Exemplary Compound A and screened for NA rescue and Naprt1 expression by immunoblotting and quantitative RT-PCR (Table 5). Of the 176 cell lines tested, 47 did not rescue, 16 partially rescued, and 113 rescued completely. 176 cell lines included 5 normal (non-cancerous) cells and 3 primitive cells (italicized in the table), all of which were rescued. Naprt1 was quantified in 164 and 123 of 176 cell lines by Western blotting and q-RT-PCR, respectively. Naprt1 levels were low or undetectable in unrescued cell lines. A statistically significant (p value <0.0001) correlation existed between the NA rescue phenotype and Naprtl protein or mRNA expression levels.

  Human tumor cell proteins were prepared from frozen cell pellets for quantification by Western blot. The cell pellet is thawed and lysed in 0.5% Triton X-100, 50 mM HEPES [pH 7.4], 150 mM NaCl, 1 mM EDTA, 10% glycerol, and 1 mM DTT for 30 minutes at 4 ° C. It was. After centrifugation to remove cell debris, the protein concentration was determined using BCA (Sigma BCA1-1KT) or CBCCA protein assay kit (Molecular Probes # C-6667). Protein loading was confirmed using Ruby Red staining of SDS-PAGE gel.

  For immunoblot detection, equivalent amounts of protein were separated by electrophoresis and transferred to a nitrocellulose membrane. Membranes were blocked in Starting Block T20 (TBS) (Thermo Scientific # 37543) and probed with anti-Naprt (Proteintech Group 13549-1-AP) antibody or anti-Gapdh (Calbiochem # CB1001) antibody. HRP-conjugated secondary antibody (Santa Cruz Biotechnology) and Super Signal West Dura Extended Duration Substrate (Thermo Scientific # 34075) were used for detection. Protein signal was quantified by imaging using the EC3 imaging system (UVP Bioimaging Systems) and VisionWorksSL software. The dynamic range of signal detection was enhanced by using multiple exposure times. Naprt protein levels were calculated as the percentage of the same line signal detected in HCT116 cell lysates.

  Untreated cell pellets were collected and lysed in RLT buffer containing 1% β-mercaptoethanol for quantification by qRT-PCR. RNA was isolated using the RNeasy spin column kit (Qiagen 74104), packed in 96-well plates in triplicate, 11 ng total RNA / well, and for NAPRT1, the QuantiTect probe RT using TaqMan primer set Hs00292993_m1 -Probed with a final sample volume of 25 ul / well using PCR kit (Qiagen 204443). Relative NAPRT expression was assayed on an Applied Biosystems 7300 Real-Time PCR system thermal cycler. The plate was heated at 50 ° C. for 30 minutes followed by 95 ° C. for 15 minutes, and then 40 cycles were repeated between 95 ° C. for 15 seconds and 60 ° C. for 1 minute. Data was collected during the 60 ° C. step of each cycle, and the cycle threshold was extrapolated to a dilution curve of total RNA from cell line SK-BR-3 to obtain a relative value of initial NAPRT mRNA concentration for each sample. The average RNA concentration for each cell line was then given as a percentage of the expression seen in cell line SK-BR-3.

  Additional cancer cell lines were treated with exemplary compounds A, C, D, E, F, G and H (identified below) (Table 6). The NA rescue phenotype of certain cancer cell lines was maintained for all Nampt inhibitors tested.

Assay of synergy between inhibitors and various chemotherapeutic compounds As mentioned above, Nampt inhibition has been shown to sensitize cells to the effects of various chemotherapeutic or cytotoxic agents. . Specifically, Nampt inhibition is achieved by treating cells with amiloride, mitomycin C, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), melphalan, daunorubicin, cytarabine (Ara-C), etoposide, and lactic acid. It has been shown to sensitize to the dehydrogenase inhibitor FX11 (Ekelund, S. et al. Chemotherapy 48: 196-204 (2002); Rongvaux, A. et al. The Journal of Immunology 181 (7): 4685-95. (2008); Martinsson, P. et al. British Journal of Pharmacology 137: 568-73 (2002); Pogrebniak, A. et al. European Journal of Medical Research 11 (8): 313-21 (2006) Le, et al., Proceedings of the National Academia of Sciences 107 (5): 2037-2042 (2010)). Although the mechanism behind this synergy between Nampt inhibitors and other cell killers has not been fully investigated, Nampt inhibition is at doses and exposure times that are not clearly toxic to cells. Causes a decrease in cellular levels of NAD ⁺ . In the case of HCT116 cells, it has been discovered that there is a “6% threshold” in which cell death does not occur until NAD ⁺ levels have dropped to about 6% of normal levels. While not wishing to be bound by theory, these non-lethal NAD ⁺ reductions make cells more resistant to other cytotoxic agents, particularly the DNA repair enzyme poly (ADP-ribose) polymerase (PARP). Is assumed to be brittle to compounds that activate. This is because PARP requires NAD ⁺ as a substrate and consumes NAD ⁺ during its enzymatic action (Kim, MY et al. Genes & Development 19: 1951-67 (2005); FIG. 1, top) .

  This hypothesis is determined by determining the drug interactions (synergism, additivity, or antagonism) of 19 different cytotoxic or chemotherapeutic compounds of various categories, together with a known Nampt inhibitor as a positive control. Tested. Nineteen chemotherapeutic compounds were selected based on their clinical reliability and potential synergy with Nampt inhibitors based on the PARP model (FIG. 1). Experiments were performed on HCT116 cells. This cell type has been widely used in the cytotoxicity studies of the compounds of the present invention. In addition, since HCT116 cells are typically used in xenograft cancer models, cell experiments provide insight into how best to perform subsequent in vivo studies of synergy. Was supposed to get. For compound combination analysis, the MacSynergy ™ II protocol and program were utilized according to developer recommendations (Prichard and Shipman, 1990). Prior to compound combination, a dose curve of cells treated with one compound was generated to determine the dose of the relevant compound to be used in the combination analysis. Typically, the relevant dose was that found in the inner bay portion of the sigmoidal dose response curve. Utilizing these optimized conditions, the cells were given Nampt inhibitor and test compound at various doses, respectively, and the viability was assessed using CellTiter-Glo. Data was processed using the MacSynergyTM II algorithm. This algorithm subtracted the predictive value of compound additivity from actual data. Significant synergy thresholds were defined based on developer recommendations (Prichard and Shipman, 1990).

Of the 19 different chemotherapeutic compounds tested, 9 showed reproducible, quantitatively significant synergies with known Nampt inhibitors. Synergistic compounds included the DNA alkylating agents methyl methanesulfonate (MMS), mechloretamine, and streptozocin (therapeutic agent for pancreatic cancer). Some alkylating agents can synergize with Nampt inhibitors due to their ability to activate PARP in cells and suppress NAD ⁺ levels (Miwa, M. and Masutani, M. Cancer) Science 98 (10): 1528-35 (2007); Kim, MY et al. Genes & Development 19: 1951-67 (2005)). Somewhat unpredictable, three clinically relevant drugs involved in nucleotide synthesis (ie, 5-fluorouracil (5-FU), raltitrexed, and methotrexate) also synergized with Nampt inhibitors. Although each of these three drugs has a different site of action, all directly or indirectly inhibit the enzyme thymidylate synthase (TS). Inactivation of TS causes an imbalance of the nucleotide pool, which subsequently promotes abnormal uracil incorporation into DNA (Berger SH et al. Biochemical Pharmacology 76: 697-706 (2008)). We investigated the mechanism of synergy between 5-FU and Nampt inhibitor, and that 5-FU in HCT116 cells is a PARP activator, and that PARP activation is related to 5-FU and Nampt inhibitor It was found to be essential for synergy between (Fig. 1A).

  Initial experiments show that 5-FU and Nampt inhibitor do not synergize in all cells tested, and in these cells lacking synergy 5-FU caused detectable PARP activation. Proved not to be. These results indicate that uptake of uracil into DNA does not occur in all cells treated with 5-FU, or PARP is activated only in specific cells in response to uptake of uracil into DNA. Suggested that either. The observation of cell-specific synergy between 5-FU and Nampt inhibitors may be therapeutically useful as a mechanism to expand the therapeutic window. Among additional considerations, the elucidated relationship between 5-FU, PARP activation, and Nampt inhibition appears to be a new discovery.

  Finally, bortezomib, a proteosome inhibitor, PI-103, a PI3K / mTOR inhibitor, and dasatinib, a tyrosine kinase inhibitor, were all observed to synergize with Nampt inhibitors. The synergy between these three compounds and the Nampt inhibitor was unpredictable.

In HCT116 cells, olaparib, a potent and selective PARP inhibitor, did not synergize with Nampt inhibitors. In practice, antagonism was observed. Here, olaparib protected the cells somewhat from death induced by Nampt inhibitors. This was not completely unpredictable. This is because PARP inhibitors are relatively benign on cells that have a functional homologous recombination (HR) system to repair double-stranded DNA damage (such as HCT116 cells) (Ashworth A. Journal of Clinical Oncology 26 (22): 3785-90 (2008)). Indeed, the model (FIG. 1A) predicts that inhibition of enzymes that consume NAD ⁺ (eg, PARP) protects HR active cells from Nampt inhibition. However, in cells that have lost BRCA tumor suppressor function, HR function is impaired and these cells are killed by PARP inhibitors (Ashworth A. (2008) Journal of Clinical Oncology 26 (22): 3785- 90). Thus, it was hypothesized that PARP inhibitors antagonize Nampt inhibitors in most cells, but are synergistic in cells with BRCA mutations that render the cells HR deficient (FIG. 1B). In fact, in MDA-MB-436 cells (losing BRCA1 function), Nampt inhibitors (Exemplary Compound A and Illustrative Compound I, which are known Nampt inhibitors, both exemplary compounds are described herein. (Identified below) and the PARP inhibitor olaparib synergized to cause cell death. This result shows that a drug combination of one of the compounds of the present invention and a PARP inhibitor antagonizes in normal cells (FIG. 1A) but synergizes in cells that have lost the BRCA tumor suppressor function (FIG. 1B). This is especially encouraging. Of these findings, it becomes clear that other pathways of HR deficiency in oncogenes (other than BRCA sequence mutations) can also lead to sensitivity to PARP inhibition and Nampt inhibitor combination therapy. ing. These additional mutations resulting in a “BRCAness” phenotype include BRCA1 promoter methylation and up-regulation of BRCA inhibitors (eg, protein EMSY) as documented in ovarian cancer (Bast RC and Mills GBJournal of Clinical Oncology 28 (22): 3545-8 (2010)). Further studies show that mutations in tumor suppressor gene phenotypes and tensin homologs (PTEN), genes that mutate frequently in various cancers, reduce HR function and sensitize cells to PARP inhibitors (Mendes-Pereira AM et al. EMBO Molecular Medicine 1: 315-322 (2009)). In cell biology studies using RNA interference, mutations in one of 12 different genes that are functionally important for HR provide additional evidence for a BRCAness model of PARP inhibitor sensitivity Cells were sensitized to PARP inhibitors (McCabe et al. Cancer Research 66 (16): 8109-15 (2006)). Finally, recent papers have shown that cells in hypoxic conditions (eg, cells found in virtually all solid tumor centers) are selectively killed by PARP inhibitors (Chan et al. Cancer) Research 70 (2): 8045-54 (2010)). Thus, there are many clinical machines in which PARP inhibitors and Nampt inhibitors are combined to treat a wide variety of cancers.

  These studies were expanded to investigate synergistic combinations of Nampt inhibitors with medical standards for specific cancer types. The cancer cell lines used in these studies represented cancer types that were found to be sensitive to Nampt inhibition [eg, non-Hodgkin lymphoma, multiple myeloma, glioma, non- Small cell lung carcinoma (NSCLC), small cell lung carcinoma (SCLC), ovarian cancer and colorectal cancer]. Medical standards in these cancer types tested in synergy experiments are 4-HC (pre-activation form of cyclophosphamide), doxorubicin, vincristine, prednisolone, dexamethasone, melphalan, thalidomide, bortezomib, temozolomide Cisplatin, paclitaxel, gefitinib, 5-FU, oxaliplatin, irinotecan, and etoposide. Synergistic cytotoxicity is a Nampt inhibitor (Exemplary Compound A and Exemplary Compound C, both identified herein below), which is associated with 4HC in small cell lung cancer (SCLC) and glioma. It was seen when combined, when combined with temozolomide in glioma, and when combined with 5-FU in colon cancer.

Nampt inhibitor probes that are cytotoxic to a wide variety of cancer cell types
Nampt is most active in visceral adipose tissue, liver, kidney, immune cells, and intestinal tract (Bogan, KL and Brenner, C. Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD ⁺ precursor vitamins in human nutrition.Annu Rev Nutr. 28: 115-305 (2008); and Revollo JR, et al. Nampt / PBEF / Visfatin regulates insulin secretion in beta cells as a systemic NAD biosynthetic enzyme.Cell Metab.Nov; 6 (5): 363 -75 (2007)). Nevertheless, we sought to find out whether other origins of cancer cell lines are sensitive to Nampt inhibition.

  Exponentially growing cells were plated in fresh growth media in 96 well black flat clear bottom polystyrene microtiter plates (Packard View Plate 6005182). After 24 hours, compounds were added from serial dilutions prepared in DMSO from a 50 mM DMSO stock solution. Each concentration of inhibitor was tested in duplicate with a final DMSO concentration of 0.4%. After 72 hours or 96 hours incubation, cell viability was quantified by measuring intracellular ATP levels using CellTiter-Glo (Promega). Luminescence data was collected on a TopCount NXT plate reader (PerkinElmer). Experimental values were normalized to solvent control and plotted against compound concentration to determine the concentration required for a 50% reduction in cell viability.

Using the cytotoxicity assay outlined above, several exemplary compounds of the invention (“Exemplary Compounds A, B, C, D, E, F, G, and H), as well as known Nampts Inhibitors (“control Nampt inhibitors”) were tested. The results are shown in Table 7A and Table 7B. Exemplary Compound A is a compound represented by Formula IIIb7. Exemplary compounds B and I are compounds represented by formula IIIb5. Exemplary compounds C, D, and H are compounds represented by Formula IIIb9. Exemplary compounds E, F, and G are compounds represented by Formula IIIb8. The killing was almost complete (> 80%) in all three compounds after 3 days and was complete in all strains after 7 days. These data demonstrate that a wide variety of cancer cell types are susceptible to killing by the compounds of the present invention. The unit is TC ₅₀ expressed as nanomolar (nM) (“toxic concentration required to produce 50% growth inhibition”).

  All publications and patent applications mentioned in the specification are indicative of the levels of those skilled in the art to which this application pertains. All publications and patent applications are hereby incorporated by reference to the same extent as if each individual publication or patent application was explicitly and individually indicated to be incorporated by reference. The mere description of these publications and patent applications does not necessarily constitute an authentication that they are prior art to the present application.

  Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be understood that certain changes and modifications may be practiced within the scope of the appended claims.

Claims (237)

Formula I:

And a pharmaceutically acceptable salt and solvate thereof, wherein in the formula I
Y is phenyl, 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl, where any ring carbon is independently halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C Optionally substituted with -amide, N-amide, C-carboxy, O-carboxy, sulfonamido, amino, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl;
Y ₁ is a divalent carbocycle, divalent heterocycle, divalent phenyl or divalent heteroaryl, wherein any ring atom is independently halo, C _1-5 alkyl, nitro, Optionally substituted with cyano, trihalomethyl, C _1-5 alkoxy, C-amide, N-amide, sulfonamido, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl, or
Y ₁ is C _2-8 alkylene or C _2-8 alkenylene, and optionally -O-, -S-, -S (= O)-, -S (= O) _2- , -OC (= O) N (R)-, -N (R) C (= O) O-, -C (= O) N (R)-, -N (R) C (= O)-, -N ( R) C (= O) N (R)-, -N (R)-, -C (= O)-, -OC (= O)-, -C (= O) O-, -OS (= O ) ₂ N (R)-, -N (R) S (= O) ₂ O-, -SC (= O)-, -C (= O) S-, -OC (= S) N (R)- , -N (R) C (= S) O-, -C (= S) N (R)-, -N (R) C (= S)-, -N (R) C (= S) N ( R)-, -C (= S)-, -OC (= S)-, -C (= S) O-, -S (= O) ₂ N (R)-, -N (R) S (= O) _2- , -S (= O) ₂ N (R) C (= O)-, or -C (= O) N (R) S (= O) _2- once, twice, or 3 Intervening times;
Y _{2 is, -OCH 2 -, - SCH 2} -, - N (R) CH 2 -, - N (R) C (= O) -, - C (= O) N (R) -, - S ( = O) ₂ CH _2- , -S (= O) CH _2- , -CH ₂ O-, -CH ₂ CH ₂ O-, -CH ₂ S-, -CH ₂ N (R)-, -CH ₂ S (= O) _2- , -CH ₂ S (= O)-, -C (= O) O-, -OC (= O)-, -SO ₂ N (R)-, -N (R) SO _2- , ethylene, propylene, n-butylene, -OC _1-4 alkylene-N (R) C (= O)-, -OC _1-4 alkylene-C (= O) N (R)-, -N ( R) C (= O) -C _1-4 alkylene-O-, -C (= O) N (R) -C _1-4 alkylene-O-, -C _1-4 alkylene-S (= O) ₂ -, -C _1-4 alkylene-S (= O)-, -S (= O) ₂ -C _1-4 alkylene-, -S (= O) -C _1-4 alkylene-, -C _1-4 alkylene _{-SO 2 N (R) -,} - C 1~4 alkylene _{-N (R) SO 2 -,} - SO 2 N (R) -C 1~4 alkylene -, - N (R) SO 2 -C 1 _{to 4} alkylene -, - C _{1 to 4} alkylene -OC _{1 to 4} alkylene -, - OC _{1 to 4} alkylene -, - C _{1 to 4} alkylene -O _-, - SC _1~4 alkylene -, - C _{1 to 4} alkylene -S _-, - C _1~4 alkylene -SC _{1 to 4} alkylene -, - N (R) -C 1~4 alkylene -, - C _{1 to 4} alkylene -N (R) -, - C 1~4 alkylene -N (R) -C _1~4 alkylene -, - C _{1 to 4} alkylene -C (= O) -OC _1~4 alkylene _-, - C 1~ ₄ alkylene-OC (= O) -C _1-4 alkylene-, -C _1-4 alkylene-C (= O) -N (R) -C _1-4 alkylene-, -C _1-4 alkylene-N ( R) -C (= O) -C _1-4 alkylene-, -C (= O) -N (R) -C _1-4 alkylene-SO ₂ N (R)-, or -N (R) -C (= O) -C _1-4 alkylene-SO ₂ N (R)-;
Z ₀ is carbocycle, cycloalkyl, cycloalkenyl, heterocycle, heterocyclonoyl, aryl, heteroaryl, carbocycloalkyl, heterocyclylalkyl, arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, Or arylalkynyl,
Wherein any of the above groups are optionally alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, carbocycle, cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl, halo, hydro, Hydroxyl, alkoxy, alkynyloxy, cycloalkyloxy, heterocyclooxy, aryloxy, heteroaryloxy, arylalkoxy, heteroarylalkoxy, mercapto, alkylthio, arylthio, arylalkyl, heteroarylalkyl, heteroarylalkenyl, arylalkynyl, haloalkyl Aldehyde, thiocarbonyl, heterocyclonoyl, O-carboxy, C-carboxy, carboxylic acid, ester, C-carboxy salt, carboxyalkyl, carboxy Lukenylene, carboxyalkyl salt, carboxyalkoxy, carboxyalkoxyalkanoyl, amino, aminoalkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amide, N-amide, aminothiocarbonyl, hydroxyamino With carbonyl, alkoxyaminocarbonyl, cyano, nitrile, cyanato, isocyanato, thiocyanato, isothiocyanate, sulfinyl, sulfonyl, sulfonamido, aminosulfonyl, aminosulfonyloxy, sulfonamidocarbonyl, alkanoylaminosulfonyl, trihalomethylsulfonyl, or trihalomethylsulfonamide Has been substituted at least once;
Where any alkylene or alkenylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
Where in Y ₁ , R is H, halo, C _1-4 alkyl, C _1-4 alkenyl, or C _1-4 alkynyl;
Where in Y ₂ R is H, halo, C _1-5 alkyl, C _1-5 alkenyl, C _1-5 alkynyl, or 5- or 6-membered together with the carbon atom of Z ₀ Methylene or ethylene forming a heterocycle; and the compound is:
3- (pyridin-3-yl) -4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) butanoic acid ethyl;
4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) -3- [4- (trifluoromethyl) phenyl] butanoic acid;
3-phenyl-4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) butanoic acid;
3- (4-Chloro-3-fluorophenyl) -4-[(4-{[3-{[(pyridin-3-ylmethyl) carbamoyl] amino} -5- (trifluoromethyl) benzyl] oxy} phenyl) Sulfonyl] butanoic acid;
3-phenyl-4-[(4-{[3-{[(pyridin-3-ylmethyl) carbamoyl] amino} -5- (trifluoromethyl) benzyl] oxy} phenyl) sulfonyl] butanoic acid;
3- (pyridin-3-yl) -4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) butanoic acid;
4-({4-[(4-Fluoro-3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) -3- (pyridin-3-yl) butanoic acid;
1,1'-butane-1,4-diylbis [3- (pyridin-3-ylmethyl) urea];
1-[(6-methoxypyridin-3-yl) methyl] -3- [3- (3-methylphenoxy) propyl] urea; or
Compounds that are not 1- [3- (2-fluorophenoxy) propyl] -3-[(6-methoxypyridin-3-yl) methyl] urea, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula Ia

According to claim 1 and pharmaceutically acceptable salts and solvates thereof according to formula Ia:
Z ₀ and Y ₂ are as defined for formula I above;
n is 3, 4, 5, 6, or 7;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₇ when present more than once replaces a hydrogen atom on the pyridinyl ring and is halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, Independently selected from C-carboxy, O-carboxy, trihalomethyl, C-carboxy, O-carboxy, sulfonamido, amino, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl;
1,1'-butane-1,4-diylbis [3- (pyridin-3-ylmethyl) urea]
Not the compounds and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula Ia1

According to claim 1 or 2 and pharmaceutically acceptable salts and solvates thereof according to formula Ia1:
Z ₀ is as defined above for formula I;
n is 3, 4, 5, 6, or 7;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl; and
R ₇ is as defined for formula Ia,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula Ia2

According to claim 1 or 2 and pharmaceutically acceptable salts and solvates thereof according to formula Ia2:
Z ₀ is as defined above for formula I;
n is 3, 4, 5, 6, or 7;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₂ is H, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl; and
R ₇ is as defined for formula Ia,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula Ib

According to claim 1, and pharmaceutically acceptable salts and solvates thereof, in formula Ib:
Z ₀ and Y ₂ are as defined for formula I above;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₆ and R ₇ are each independently halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide Selected from, amino, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl; and
S, T, U, and V are carbon or nitrogen, provided that when S, T, U, or V is nitrogen, there are no substituents on the nitrogen;
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula Ib1

According to claim 1 or 5, and pharmaceutically acceptable salts and solvates thereof, in formula Ib1:
Z ₀ is as defined above for formula I;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₃ and R ₄ are each independently H or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which they are attached form a cyclopropyl or cyclobutyl ring. Forming; and
R ₆ and R ₇ are as defined for formula Ib above,
Compounds, and pharmaceutically acceptable salts and solvates thereof. The structure is Ib2

According to claim 1 or 5, and pharmaceutically acceptable salts and solvates thereof, in Ib2:
Z ₀ is as defined above for formula I;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₂ is H, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl; and
R ₆ and R ₇ are as defined for formula Ib above,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula Ib3

According to claim 1 or 5, and pharmaceutically acceptable salts and solvates thereof, in formula Ib3:
Z ₀ is as defined above for formula I;
u is 0 or 1;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl; and
R ₆ and R ₇ are as defined for formula Ib above,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula Ic

According to claim 1, and pharmaceutically acceptable salts and solvates thereof, in formula Ic:
Z ₀ and Y ₁ are as defined for formula I above;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₃ and R ₄ are each independently H or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which they are attached form a cyclopropyl or cyclobutyl ring. Forming;
R ₇ when present more than once replaces a hydrogen atom on the pyridinyl ring and is halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, Independently selected from C-carboxy, O-carboxy, sulfonamido, amino, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl;
3- (pyridin-3-yl) -4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) butanoic acid ethyl;
4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) -3- [4- (trifluoromethyl) phenyl] butanoic acid;
3-phenyl-4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) butanoic acid;
3- (4-Chloro-3-fluorophenyl) -4-[(4-{[3-{[(pyridin-3-ylmethyl) carbamoyl] amino} -5- (trifluoromethyl) benzyl] oxy} phenyl) Sulfonyl] butanoic acid;
3-phenyl-4-[(4-{[3-{[(pyridin-3-ylmethyl) carbamoyl] amino} -5- (trifluoromethyl) benzyl] oxy} phenyl) sulfonyl] butanoic acid;
3- (pyridin-3-yl) -4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) butanoic acid; or
4-({4-[(4-fluoro-3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) -3- (pyridin-3-yl) butanoic acid, Compounds, and pharmaceutically acceptable salts and solvates thereof. The structure is of formula Id

According to claim 1, and pharmaceutically acceptable salts and solvates thereof, in formula Id:
Z ₀ and Y ₁ are as defined for formula I above;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₂ is H, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl; and
R ₇ when present more than once replaces a hydrogen atom on the pyridinyl ring and is halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, Independently selected from C-carboxy, O-carboxy, sulfonamido, amino, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Formula II

And the pharmaceutically acceptable salts and solvates thereof, in Formula II:
Z is hydro, halo, _C1-5 alkyl, nitro, cyano, _C1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, trihalomethyl, C-carboxy, O -Carboxy, sulfonamido, amino, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl, where _C1-5 alkyl, _C1-5 alkoxy, C-amide, N-amido, amino, and alkylthio are each Optionally substituted with heterocyclo, cycloalkyl, or amino; or
Z is carbocycle, cycloalkyl, cycloalkenyl, heterocycle, heterocyclonoyl, aryl, heteroaryl, carbocycloalkyl, heterocyclylalkyl, arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, or Arylalkynyl, wherein any of the above groups are optionally alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, carbocycle, cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl , Halo, hydro, hydroxyl, alkoxy, alkynyloxy, cycloalkyloxy, heterocyclooxy, aryloxy, heteroaryloxy, arylalkoxy, heteroarylal Koxy, mercapto, alkylthio, arylthio, arylalkyl, heteroarylalkyl, heteroarylalkenyl, arylalkynyl, haloalkyl, aldehyde, thiocarbonyl, heterocyclonoyl, O-carboxy, C-carboxy, carboxylic acid, ester, C-carboxy salt , Carboxyalkyl, carboxyalkenylene, carboxyalkyl salt, carboxyalkoxy, carboxyalkoxyalkanoyl, amino, aminoalkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amide, N-amide, amino Thiocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, cyano, nitrile, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulf Sulfonyl, sulfonamido, aminosulfonyl, amino sulfonyloxy, sulfonamido carbonyl, alkanoylamino sulfonyl is substituted at least once with a trihalomethyl sulfonyl or trihalomethyl sulfonamide;
Y is phenyl, 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl, where any ring carbon is independently halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C Optionally substituted with -amide, N-amide, C-carboxy, O-carboxy, sulfonamido, amino, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl;
Y ₁ is a divalent carbocycle, divalent heterocycle, divalent phenyl or divalent heteroaryl, wherein any ring atom is independently halo, C _1-5 alkyl, nitro, Optionally substituted with cyano, trihalomethyl, C _1-5 alkoxy, C-amide, N-amide, sulfonamido, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl, or
Y ₁ is C _2-8 alkylene or C _2-8 alkenylene, and optionally -O-, -S-, -S (= O)-, -S (= O) _2- , -OC (= O) N (R)-, -N (R) C (= O) O-, -C (= O) N (R)-, -N (R) C (= O)-, -N ( R) C (= O) N (R)-, -N (R)-, -C (= O)-, -OC (= O)-, -C (= O) O-, -OS (= O ) ₂ N (R)-, -N (R) S (= O) ₂ O-, -SC (= O)-, -C (= O) S-, -OC (= S) N (R)- , -N (R) C (= S) O-, -C (= S) N (R)-, -N (R) C (= S)-, -N (R) C (= S) N ( R)-, -C (= S)-, -OC (= S)-, -C (= S) O-, -S (= O) ₂ N (R)-, -N (R) S (= O) _2- , -S (= O) ₂ N (R) C (= O)-, or -C (= O) N (R) S (= O) _2- once, twice, or 3 Intervening times;
Y _{2 is, -OCH 2 -, - SCH 2} -, - N (R) CH 2 -, - N (R) C (= O) -, - C (= O) N (R) -, - S ( = O) ₂ CH _2- , -S (= O) CH _2- , -CH ₂ O-, -CH ₂ CH ₂ O-, -CH ₂ S-, -CH ₂ N (R)-, -CH ₂ S (= O) _2- , -CH ₂ S (= O)-, -C (= O) O-, -OC (= O)-, -SO ₂ N (R)-, -N (R) SO _2- , ethylene, propylene, n-butylene, -OC _1-4 alkylene-N (R) C (= O)-, -OC _1-4 alkylene-C (= O) N (R)-, -N ( R) C (= O) -C _1-4 alkylene-O-, -C (= O) N (R) -C _1-4 alkylene-O-, -C _1-4 alkylene-S (= O) ₂ -, -C _1-4 alkylene-S (= O)-, -S (= O) ₂ -C _1-4 alkylene-, -S (= O) -C _1-4 alkylene-, -C _1-4 alkylene _{-SO 2 N (R) -,} - C 1~4 alkylene _{-N (R) SO 2 -,} - SO 2 N (R) -C 1~4 alkylene -, - N (R) SO 2 -C 1 _{to 4} alkylene -, - C _{1 to 4} alkylene -OC _{1 to 4} alkylene -, - OC _{1 to 4} alkylene -, - C _{1 to 4} alkylene -O _-, - SC _1~4 alkylene -, - C _{1 to 4} alkylene -S _-, - C _1~4 alkylene -SC _{1 to 4} alkylene -, - N (R) -C 1~4 alkylene -, - C _{1 to 4} alkylene -N (R) -, - C 1~4 alkylene -N (R) -C _1~4 alkylene -, - C _{1 to 4} alkylene -C (= O) -OC _1~4 alkylene _-, - C 1~ ₄ alkylene-OC (= O) -C _1-4 alkylene-, -C _1-4 alkylene-C (= O) -N (R) -C _1-4 alkylene-, -C _1-4 alkylene-N ( R) -C (= O) -C _1-4 alkylene-, -C (= O) -N (R) -C _1-4 alkylene-SO ₂ N (R)-, or -N (R) -C (= O) -C _1-4 alkylene-SO ₂ N (R)-;
Where in Y ₁ , R is H, halo, C _1-4 alkyl, C _1-4 alkenyl, or C _1-4 alkynyl;
Where in Y ₂ R is H, C _1-5 alkyl, C _1-5 alkenyl, C _1-5 alkynyl or a 5- or 6-membered heterocycle together with the carbon atom of Y ₃ Methylene or ethylene to form;
Y ₃ is aryl or heteroaryl, wherein any ring carbon is independently halo, C _1-5 alkyl, nitro, cyano, trihalomethyl, C _1-5 alkoxy, C-amide, N-amide , Sulfonamide, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl, optionally substituted, where C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide , Amino, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
Any alkylene or alkenylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl; and the compound is :
1-[(6-methoxypyridin-3-yl) methyl] -3- [3- (3-methylphenoxy) propyl] urea;
1- [3- (2-fluorophenoxy) propyl] -3-[(6-methoxypyridin-3-yl) methyl] urea;
3- (pyridin-3-yl) -4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) butanoic acid ethyl;
4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) -3- [4- (trifluoromethyl) phenyl] butanoic acid;
3-phenyl-4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) butanoic acid;
3- (4-Chloro-3-fluorophenyl) -4-[(4-{[3-{[(pyridin-3-ylmethyl) carbamoyl] amino} -5- (trifluoromethyl) benzyl] oxy} phenyl) Sulfonyl] butanoic acid;
3-phenyl-4-[(4-{[3-{[(pyridin-3-ylmethyl) carbamoyl] amino} -5- (trifluoromethyl) benzyl] oxy} phenyl) sulfonyl] butanoic acid;
3- (pyridin-3-yl) -4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) butanoic acid; or
4-({4-[(4-fluoro-3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) -3- (pyridin-3-yl) butanoic acid, Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIa

According to claim 11, and pharmaceutically acceptable salts and solvates thereof, according to formula IIa
Z, Y ₂ and Y ₃ are as defined for Formula II above;
n is 3, 4, 5, 6, or 7;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl; and
R ₇ when present more than once replaces a hydrogen atom on the pyridinyl ring and is halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, Independently selected from C-carboxy, O-carboxy, sulfonamido, amino, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIa1

According to claim 11 or 12, and pharmaceutically acceptable salts and solvates thereof, in formula IIa1:
Z and Y ₃ are as defined for Formula II above;
n is 3, 4, 5, 6, or 7;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl; and
R ₇ is as defined for Formula IIa above,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIa3

14. A compound according to any one of claims 11 to 13, and pharmaceutically acceptable salts and solvates thereof, according to formula IIa3:
Z is as defined for Formula II above;
n is 3, 4, 5, 6, or 7;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino; and
R ₇ is as defined for Formula IIa above,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIa2

According to claim 11 or 12, and pharmaceutically acceptable salts and solvates thereof, in formula IIa2:
Z and Y ₃ are as defined for Formula II above;
n is 3, 4, 5, 6, or 7;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₂ is H, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl; and
R ₇ is as defined for Formula IIa above,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIa4

According to claim 11, 12, or 15, and pharmaceutically acceptable salts and solvates thereof, in formula IIa4:
Z is as defined for Formula II above;
n is 3, 4, 5, 6, or 7;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₂ is H, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl; and
R ₇ is as defined for Formula IIa above,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIb

According to claim 11 and pharmaceutically acceptable salts and solvates thereof according to formula IIb:
Z, Y ₂ and Y ₃ are as defined for Formula II above,
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₆ and R ₇ are each independently halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide Selected from, amino, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl; and
S, T, U, and V are carbon or nitrogen, provided that when S, T, U, or V is nitrogen, there are no substituents on the nitrogen;
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIb1

According to claim 11 or 17, and pharmaceutically acceptable salts and solvates thereof, in formula IIb1:
Z and Y ₃ are as defined for Formula II above,
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₃ and R ₄ are each independently H or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which they are attached form a cyclopropyl or cyclobutyl ring. Forming; and
R ₆ and R ₇ are as defined for Formula IIb above,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIb4

According to claim 11, 17, or 18, and pharmaceutically acceptable salts and solvates thereof, in formula IIb4:
Z is as defined for Formula II above;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₃ and R ₄ are each independently H or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which they are attached form a cyclopropyl or cyclobutyl ring. Forming; and
R ₆ and R ₇ are as defined for Formula IIb above,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIb2

According to claim 11 or 17, and pharmaceutically acceptable salts and solvates thereof, in formula IIb2:
Z and Y ₃ are as defined for Formula II above;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₂ is H, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl; and
R ₆ and R ₇ are as defined for Formula IIb above,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIb5

According to claim 11, 17, or 20, and pharmaceutically acceptable salts and solvates thereof, in formula IIb5:
Z is as defined for Formula II above;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₂ is H, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl; and
R ₆ and R ₇ are as defined for Formula IIb above,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIb3

According to claim 11 or 17, and pharmaceutically acceptable salts and solvates thereof, in formula IIb3:
Z and Y ₃ are as defined for Formula II above,
u is 0 or 1;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl; and
R ₆ and R ₇ are as defined for Formula IIb above,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIb6

According to claim 11, 17, or 22, and pharmaceutically acceptable salts and solvates thereof, in Formula IIb6:
Z is as defined for Formula II above;
u is 0 or 1;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino; and
R ₆ and R ₇ are as defined for Formula IIb above,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIb7

According to claim 11 or 17, and pharmaceutically acceptable salts and solvates thereof, in formula IIb7:
Z and Y ₂ are as defined for Formula II above;
Any methylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino; and
R ₆ and R ₇ are as defined for Formula IIb above,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIc

According to claim 11 and pharmaceutically acceptable salts and solvates thereof according to formula IIc:
Z, Y ₁ and Y ₃ are as defined for Formula II above;
Any alkylene or alkenylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₃ and R ₄ are each independently H or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which they are attached form a cyclopropyl or cyclobutyl ring. Forming; and
R ₇ when present more than once replaces a hydrogen atom on the pyridinyl ring and is halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, Independently selected from C-carboxy, O-carboxy, sulfonamido, amino, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIc1

According to claim 11 or 25, and pharmaceutically acceptable salts and solvates thereof, in formula IIc1:
Z and Y ₁ are as defined in Formula II above;
Any alkylene or alkenylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₁ is halo, C _1-5 alkyl, nitro, cyano, alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide, amino, amino when present more than once Independently selected from alkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, and alkylthio are Each optionally substituted with heterocyclo, cycloalkyl, or amino; and
R ₃ , R ₄ , and R ₇ are as defined for Formula IIc,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IId

According to claim 11 and pharmaceutically acceptable salts and solvates thereof according to formula IId:
Z, Y ₁ and Y ₃ are as defined for Formula II above;
Any alkylene or alkenylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₂ is H, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl; and
R ₇ when present more than once replaces a hydrogen atom on the pyridinyl ring and is halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, Independently selected from C-carboxy, O-carboxy, sulfonamido, amino, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IId1

According to claim 11 or 27, and pharmaceutically acceptable salts and solvates thereof, in formula IId1:
Z and Y ₁ are as defined for Formula II above;
Any alkylene or alkenylene group is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino; and
R ₂ and R ₇ are as defined for Formula IId,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Formula III

And the pharmaceutically acceptable salts and solvates thereof, in Formula III:
Y is phenyl, 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl, where any ring carbon is independently halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C Optionally substituted with -amide, N-amide, C-carboxy, O-carboxy, sulfonamido, amino, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl;
Y ₁ is a divalent carbocycle, divalent heterocycle, divalent phenyl or divalent heteroaryl, wherein any ring atom is independently halo, C _1-5 alkyl, nitro, Optionally substituted with cyano, trihalomethyl, C _1-5 alkoxy, C-amide, N-amide, sulfonamido, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl, or
Y ₁ is C _2-8 alkylene or C _2-8 alkenylene, and optionally -O-, -S-, -S (= O)-, -S (= O) _2- , -OC (= O) N (R)-, -N (R) C (= O) O-, -C (= O) N (R)-, -N (R) C (= O)-, -N ( R) C (= O) N (R)-, -N (R)-, -C (= O)-, -OC (= O)-, -C (= O) O-, -OS (= O ) ₂ N (R)-, -N (R) S (= O) ₂ O-, -SC (= O)-, -C (= O) S-, -OC (= S) N (R)- , -N (R) C (= S) O-, -C (= S) N (R)-, -N (R) C (= S)-, -N (R) C (= S) N ( R)-, -C (= S)-, -OC (= S)-, -C (= S) O-, -S (= O) ₂ N (R)-, -N (R) S (= O) _2- , -S (= O) ₂ N (R) C (= O)-, or -C (= O) N (R) S (= O) _2- once, twice, or 3 Intervening times;
Where in Y ₁ , R is H, halo, C _1-4 alkyl, C _1-4 alkenyl, or C _1-4 alkynyl;
Y _{2 is, -OCH 2 -, - SCH 2} -, - N (R) CH 2 -, - N (R) C (= O) -, - C (= O) N (R) -, - S ( = O) ₂ CH _2- , -S (= O) CH _2- , -CH ₂ O-, -CH ₂ CH ₂ O-, -CH ₂ S-, -CH ₂ N (R)-, -CH ₂ S (= O) _2- , -CH ₂ S (= O)-, -C (= O) O-, -OC (= O)-, -SO ₂ N (R)-, -N (R) SO _2- , ethylene, propylene, n-butylene, -OC _1-4 alkylene-N (R) C (= O)-, -OC _1-4 alkylene-C (= O) N (R)-, -N ( R) C (= O) -C _1-4 alkylene-O-, -C (= O) N (R) -C _1-4 alkylene-O-, -C _1-4 alkylene-S (= O) ₂ -, -C _1-4 alkylene-S (= O)-, -S (= O) ₂ -C _1-4 alkylene-, -S (= O) -C _1-4 alkylene-, -C _1-4 alkylene _{-SO 2 N (R) -,} - C 1~4 alkylene _{-N (R) SO 2 -,} - SO 2 N (R) -C 1~4 alkylene -, - N (R) SO 2 -C 1 _{to 4} alkylene -, - C _{1 to 4} alkylene -OC _{1 to 4} alkylene -, - OC _{1 to 4} alkylene -, - C _{1 to 4} alkylene -O _-, - SC _1~4 alkylene -, - C _{1 to 4} alkylene -S _-, - C _1~4 alkylene -SC _{1 to 4} alkylene -, - N (R) -C 1~4 alkylene -, - C _{1 to 4} alkylene -N (R) -, - C 1~4 alkylene -N (R) -C _1~4 alkylene -, - C _{1 to 4} alkylene -C (= O) -OC _1~4 alkylene _-, - C 1~ ₄ alkylene-OC (= O) -C _1-4 alkylene-, -C _1-4 alkylene-C (= O) -N (R) -C _1-4 alkylene-, -C _1-4 alkylene-N ( R) -C (= O) -C _1-4 alkylene-, -C (= O) -N (R) -C _1-4 alkylene-SO ₂ N (R)-, or -N (R) -C (= O) -C _1-4 alkylene-SO ₂ N (R)-;
Where in Y ₂ R is H, C _1-5 alkyl, C _1-5 alkenyl, C _1-5 alkynyl or a 5- or 6-membered heterocycle together with the carbon atom of Y ₃ Methylene or ethylene to form;
Y ₃ is aryl or heteroaryl, wherein any ring carbon is independently halo, C _1-5 alkyl, nitro, cyano, trihalomethyl, C _1-5 alkoxy, C-amide, N-amide , Sulfonamide, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl, optionally substituted, where C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide , Amino, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
Y ₄ is optionally present and, when present, is an aryl, heteroaryl, carbocycle, or heterocycle, wherein any ring atom is independently halo, C _1-5 alkyl, nitro , Cyano, trihalomethyl, C _1-5 alkoxy, C-amide, N-amide, sulfonamido, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, sulfinyl, optionally substituted, where C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
o, p, and q are each independently 0, 1, or 2;
o region, p region, and q region, and any alkylene or alkenylene group Y ₂ is unsubstituted C _{1 to 4} alkyl, halo, unsubstituted C _{1 to 4} haloalkyl or unsubstituted C ₃ or C ₄ cycloalkyl, Optionally substituted with alkyl;
However, p is 0, Y ₁ is divalent phenyl, Y ₂ is -C (= O) N (H)-or -OC (H) ₂ C (= O) N (H)- And when Y ₃ is phenyl or pyridinyl, either Y ₄ is present or any substituent on Y ₃ is not —C (═O) NH ₂ ; and The compound is:
1- (6-methoxy-3-pyridyl) -3-[[4- (3-pyridylmethoxy) phenyl] methyl] urea;
1-[(6-methoxypyridin-3-yl) methyl] -3- [3- (3-methylphenoxy) propyl] urea;
1- [3- (2-fluorophenoxy) propyl] -3-[(6-methoxypyridin-3-yl) methyl] urea;
3- (pyridin-3-yl) -4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) butanoic acid ethyl;
4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) -3- [4- (trifluoromethyl) phenyl] butanoic acid;
3-phenyl-4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) butanoic acid;
3- (4-Chloro-3-fluorophenyl) -4-[(4-{[3-{[(pyridin-3-ylmethyl) carbamoyl] amino} -5- (trifluoromethyl) benzyl] oxy} phenyl) Sulfonyl] butanoic acid;
3-phenyl-4-[(4-{[3-{[(pyridin-3-ylmethyl) carbamoyl] amino} -5- (trifluoromethyl) benzyl] oxy} phenyl) sulfonyl] butanoic acid;
3- (pyridin-3-yl) -4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) butanoic acid;
4-({4-[(4-Fluoro-3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) -3- (pyridin-3-yl) butanoic acid;
Benzoic acid, 2-hydroxy-4-[[((3-pyridinylamino) carbonyl] amino]-, phenyl ester;
Benzamide, N- (3-amino-4-pyridinyl) -4-[[[[[(3-pyridinylmethyl) amino] carbonyl] amino] methyl]-;
Benzamide, N- (2-amino-3-pyridinyl) -4-[[[[[(3-pyridinylmethyl) amino] carbonyl] amino] methyl]-;
Benzamide, N- (2-amino-5-fluorophenyl) -4-[[[[[(3-pyridinylmethyl) amino] carbonyl] amino] methyl]-;
Benzamide, N- (2-hydroxyphenyl) -4-[[[[[(3-pyridinylmethyl) amino] carbonyl] amino] methyl]-;
Benzamide, N- (2-amino-5-chlorophenyl) -4-[[[[[(3-pyridinylmethyl) amino] carbonyl] amino] methyl]-;
Benzamide, 2-chloro-5-nitro-N- [4-[[(4-pyridinylamino) carbonyl] amino] phenyl]-;
Benzamide, N- [4-[[[3- (diethylamino) propyl] amino] carbonyl] phenyl] -4-[[(3-pyridinylamino) carbonyl] amino]-;
Benzamide, N- (2-aminophenyl) -4-[[[[(3-pyridinylamino) carbonyl] amino] methyl]-;
Benzamide, N- (2-aminophenyl) -4- [2-[[[[(3-pyridinylmethyl) amino] carbonyl] amino] ethyl]-;
Benzamide, N- (2-aminophenyl) -4-[[[[[(3-pyridinylmethyl) amino] carbonyl] amino] methyl]-;
Benzoic acid, 2-hydroxy-4-[[((3-pyridinylamino) carbonyl] amino]-, phenyl ester;
1,3-benzenedicarboxamide, N, N'-bis [3- (diethylamino) propyl] -5-[[4-[[(4-pyridinylamino) carbonyl] amino] benzoyl] amino]-;
Urea, N- [4- (phenylmethoxy) phenyl] -N '-[2- (3-pyridinyl) ethyl]-;
Urea, N- [4- (phenylmethoxy) phenyl] -N'-3-pyridinyl-;
Urea, N- (6-methyl-3-pyridinyl) -N '-[2- [2- (phenylmethoxy) phenyl] ethyl]-;
Urea, N- (6-methoxy-3-pyridinyl) -N '-[4- (phenylmethoxy) phenyl]-;
4,6-pyrimidinedicarboxamide, N4-[[4-[[[(2,6-dichloro-4-pyridinyl) amino] carbonyl] amino] phenyl] methyl] -N6-[(3-methoxyphenyl) methyl] -;
Benzenesulfonamide, 4-fluoro-N- [4-[[(3-pyridinylamino) carbonyl] amino] phenyl]-; or hexaneamide, 2- [2,4-bis (1,1-dimethylpropyl) phenoxy] -N- [2-chloro-4-[[[(2-chloro-3-pyridinyl) amino] carbonyl] amino] -5-hydroxyphenyl]-
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIIa

According to claim 29, and pharmaceutically acceptable salts and solvates thereof, in formula IIIa:
Y is 3-pyridinyl or 4-pyridinyl, wherein any ring carbon is independently halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, Optionally substituted with C-carboxy, O-carboxy, sulfonamido, amino, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl;
Y ₂ , Y ₃ , Y ₄ , and q are as defined in claim 29;
n is 3, 4, 5, 6, or 7; and
Any methylene group in Y ₂ and the n and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIIa1

According to claim 29 or 30, and pharmaceutically acceptable salts and solvates thereof, in formula IIIa1:
Y is as defined in claim 30;
Y ₃ , Y ₄ , and q are as defined in claim 29;
n is 3, 4, 5, 6, or 7;
any methylene group in the n and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl; and
R ₃ and R ₄ are each independently H, halo, or C _1-4 alkyl, or R ₃ and R ₄ together form a cyclopropyl ring or a cyclobutyl ring,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIIa3

A compound according to any one of claims 29 to 31 and pharmaceutically acceptable salts and solvates thereof according to formula IIIa3:
Y is as defined in claim 30;
Y ₄ and q are as defined in claim 29;
n is 3, 4, 5, 6, or 7;
any methylene group in the n and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino; and
R ₃ and R ₄ are each independently H, halo, or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which they are attached, a cyclopropyl ring or Forming a cyclobutyl ring,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIIa5

A compound according to any one of claims 29 to 32, and pharmaceutically acceptable salts and solvates thereof, according to formula IIIa5:
Y is as defined in claim 30;
q is as defined for Formula III above;
n is 3, 4, 5, 6, or 7;
any methylene group in the n and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₁ and R ₅ , when one or both are present more than once, are each independently halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalo Selected from methyl, C-carboxy, O-carboxy, sulfonamido, amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amido, amino, aminoalkyl, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino; and
R ₃ and R ₄ are each independently H, halo, or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which they are attached, a cyclopropyl ring or Forming a cyclobutyl ring,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIIa2

According to claim 29 or 30, and pharmaceutically acceptable salts and solvates thereof, in formula IIIa2:
Y is as defined in claim 30;
Y ₃ , Y ₄ , and q are as defined in claim 29;
n is 3, 4, 5, 6, or 7;
any methylene group in the n and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl; and
R ₂ is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIIa4

A compound according to any one of claims 29, 30, or 34, and pharmaceutically acceptable salts and solvates thereof, according to formula IIIa4:
Y is as defined in claim 30;
Y ₄ and q are as defined in claim 29;
n is 3, 4, 5, 6, or 7;
any methylene group in the n and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino; and
R ₂ is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIIa6

A compound according to any one of claims 29, 30, 34, or 35, and pharmaceutically acceptable salts and solvates thereof, according to formula IIIa6:
Y is as defined in claim 30;
q is as defined for Formula III above;
n is 3, 4, 5, 6, or 7;
any methylene group in the n and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino; and
R ₂ is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIIb

According to claim 29 and pharmaceutically acceptable salts and solvates thereof according to formula IIIb:
Y is 3-pyridinyl or 4-pyridinyl, wherein any ring carbon is independently halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, Optionally substituted with C-carboxy, O-carboxy, sulfonamido, amino, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl;
o, p, q, Y ₂ , Y ₃ , and Y ₄ are as defined in claim 29;
o, p, and q regions and any methylene group in Y ₂ are independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. Have been;
R ₆ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide Independently selected from, amino, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl;
Where S, T, U, and V are carbon or nitrogen, provided that when S, T, U, or V is nitrogen, there are no substituents on the nitrogen;
Where p is 0, Y ₂ is —C (═O) N (H) — or —OC (H) ₂ C (═O) N (H) —, and Y ₃ is phenyl or pyridinyl In certain instances, either Y ₄ is present or any substituent on Y ₃ is not -C (= O) NH ₂ ; and
1- (6-methoxy-3-pyridyl) -3-[[4- (3-pyridylmethoxy) phenyl] methyl] urea,
3- (pyridin-3-yl) -4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) butanoic acid ethyl;
4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) -3- [4- (trifluoromethyl) phenyl] butanoic acid;
3-phenyl-4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) butanoic acid;
3- (4-Chloro-3-fluorophenyl) -4-[(4-{[3-{[(pyridin-3-ylmethyl) carbamoyl] amino} -5- (trifluoromethyl) benzyl] oxy} phenyl) Sulfonyl] butanoic acid;
3-phenyl-4-[(4-{[3-{[(pyridin-3-ylmethyl) carbamoyl] amino} -5- (trifluoromethyl) benzyl] oxy} phenyl) sulfonyl] butanoic acid;
3- (pyridin-3-yl) -4-({4-[(3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) butanoic acid;
4-({4-[(4-Fluoro-3-{[(pyridin-3-ylmethyl) carbamoyl] amino} benzyl) oxy] phenyl} sulfonyl) -3- (pyridin-3-yl) butanoic acid;
Benzoic acid, 2-hydroxy-4-[[(3-pyridinylamino) carbonyl] amino]-, phenyl ester,
Benzamide, N- (3-amino-4-pyridinyl) -4-[[[[[(3-pyridinylmethyl) amino] carbonyl] amino] methyl]-,
Benzamide, N- (2-amino-3-pyridinyl) -4-[[[[[(3-pyridinylmethyl) amino] carbonyl] amino] methyl]-,
Benzamide, N- (2-amino-5-fluorophenyl) -4-[[[[[(3-pyridinylmethyl) amino] carbonyl] amino] methyl]-,
Benzamide, N- (2-hydroxyphenyl) -4-[[[[[(3-pyridinylmethyl) amino] carbonyl] amino] methyl]-,
Benzamide, N- (2-amino-5-chlorophenyl) -4-[[[[[(3-pyridinylmethyl) amino] carbonyl] amino] methyl]-,
Benzamide, 2-chloro-5-nitro-N- [4-[[(4-pyridinylamino) carbonyl] amino] phenyl]-,
Benzamide, N- [4-[[[3- (diethylamino) propyl] amino] carbonyl] phenyl] -4-[[((3-pyridinylamino) carbonyl] amino]-,
Benzamide, N- (2-aminophenyl) -4-[[[[(3-pyridinylamino) carbonyl] amino] methyl]-,
Benzamide, N- (2-aminophenyl) -4- [2-[[[[(3-pyridinylmethyl) amino] carbonyl] amino] ethyl]-,
Benzamide, N- (2-aminophenyl) -4-[[[[[(3-pyridinylmethyl) amino] carbonyl] amino] methyl]-,
Benzoic acid, 2-hydroxy-4-[[(3-pyridinylamino) carbonyl] amino]-, phenyl ester,
1,3-benzenedicarboxamide, N, N′-bis [3- (diethylamino) propyl] -5-[[4-[[(4-pyridinylamino) carbonyl] amino] benzoyl] amino]-,
Urea, N- [4- (phenylmethoxy) phenyl] -N ′-[2- (3-pyridinyl) ethyl]-,
Urea, N- [4- (phenylmethoxy) phenyl] -N'-3-pyridinyl-,
Urea, N- (6-methyl-3-pyridinyl) -N '-[2- [2- (phenylmethoxy) phenyl] ethyl]-,
Urea, N- (6-methoxy-3-pyridinyl) -N ′-[4- (phenylmethoxy) phenyl]-,
4,6-pyrimidinedicarboxamide, N4-[[4-[[[(2,6-dichloro-4-pyridinyl) amino] carbonyl] amino] phenyl] methyl] -N6-[(3-methoxyphenyl) methyl] -,
Benzenesulfonamide, 4-fluoro-N- [4-[[(3-pyridinylamino) carbonyl] amino] phenyl]-, or hexaneamide, 2- [2,4-bis (1,1-dimethylpropyl) phenoxy] -N- [2-chloro-4-[[[(2-chloro-3-pyridinyl) amino] carbonyl] amino] -5-hydroxyphenyl]-
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIIb1

According to claim 29 or 37, and pharmaceutically acceptable salts and solvates thereof, in formula IIIb1:
Y and R ₆ are as defined in claim 37;
o, p, q, Y ₃ , and Y ₄ are as defined in claim 29;
Any methylene group in the o, p, and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. ; And
R ₃ and R ₄ are each independently H, halo, or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which they are attached, a cyclopropyl ring or Forming a cyclobutyl ring,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIIb4

According to claim 29, 37 or 38, and pharmaceutically acceptable salts and solvates thereof, in formula IIIb4:
Y and R ₆ are as defined in claim 37;
o, p, q, and Y ₄ are as defined in claim 29;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₃ and R ₄ are each independently H, halo, or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which they are attached, a cyclopropyl ring or Forming a cyclobutyl ring; and
Any methylene group in the o, p, and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. ,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIIb7

According to claim 29 or 38, 39, and pharmaceutically acceptable salts and solvates thereof, in formula IIIb7:
Y and R ₆ are as defined in claim 37;
o, p, and q are as defined in claim 29;
R ₁ and R ₅ , when one or both are present more than once, are each independently halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalo Selected from methyl, C-carboxy, O-carboxy, sulfonamido, amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amido, amino, aminoalkyl, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₃ and R ₄ are each independently H, halo, or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which they are attached, a cyclopropyl ring or Forming a cyclobutyl ring; and
Any methylene group in the o, p, and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. ,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIIb2

According to claim 29 or 37, and pharmaceutically acceptable salts and solvates thereof, in formula IIIb2:
Y and R ₆ are as defined in claim 37;
o, p, q, Y ₃ , and Y ₄ are as defined in claim 29;
Any methylene group in the o, p, and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. ; And
R ₂ is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIIb5

According to claim 29, 37 or 41, and pharmaceutically acceptable salts and solvates thereof, in formula IIIb5:
Y and R ₆ are as defined in claim 37;
o, p, q, and Y ₄ are as defined in claim 29;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₂ is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl; and
Any methylene group in the o, p, and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. ,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIIb8

According to claim 29, 37, 41, or 42, and pharmaceutically acceptable salts and solvates thereof, in Formula IIIb8:
Y and R ₆ are as defined in claim 37;
o, p, and q are as defined in claim 29;
R ₁ and R ₅ , when one or both are present more than once, are each independently halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalo Selected from methyl, C-carboxy, O-carboxy, sulfonamido, amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amido, amino, aminoalkyl, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₂ is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl; and
Any methylene group in the o, p, and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. ,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIIb3

According to claim 29 or 37, and pharmaceutically acceptable salts and solvates thereof, in formula IIIb3:
Y and R ₆ are as defined in claim 37;
o, p, q, Y ₃ , and Y ₄ are as defined in claim 29;
u is 0 or 1; and
Any methylene group in the o, p, q, and u regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. Being
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIIb6

According to claim 29, 37, or 44, and pharmaceutically acceptable salts and solvates thereof, in formula IIIb6:
Y and R ₆ are as defined in claim 37;
o, p, q, and Y ₄ are as defined in claim 29;
u is 0 or 1;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino; and
Any methylene group in the o, p, q, and u regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. Being
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIIb9

According to claim 29, 37, 44, or 45, and pharmaceutically acceptable salts and solvates thereof, in formula IIIb9:
Y and R ₆ are as defined in claim 37;
o, p, and q are as defined in claim 29;
u is 0 or 1;
R ₁ and R ₅ , when one or both are present more than once, are each independently halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalo Selected from methyl, C-carboxy, O-carboxy, sulfonamido, amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amido, amino, aminoalkyl, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino; and
Any methylene group in the o, p, q, and u regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. Being
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIIb10

According to claim 29 or 37, and pharmaceutically acceptable salts and solvates thereof, in formula IIIb10:
Y and R ₆ are as defined in claim 37;
o, p, and q are as defined in claim 29;
R ₁ and R ₅ , when one or both are present more than once, are each independently halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalo Selected from methyl, C-carboxy, O-carboxy, sulfonamido, amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amido, amino, aminoalkyl, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₃ and R ₄ are each independently H, halo, or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which they are attached, a cyclopropyl or cyclobutyl ring Forming;
R ₆ is as defined for Formula IIIb above;
Any methylene group in the o, p, and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. ; And
S, T, U, and V are carbon or nitrogen, provided that at least one of S, T, U, and V is nitrogen and S, T, U, or V is nitrogen If no substituent is present on the nitrogen,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIIb11

According to claim 29 or 37, and pharmaceutically acceptable salts and solvates thereof, in formula IIIb11:
Y and R ₆ are as defined in claim 37;
o, p, and q are as defined in claim 29;
R ₁ is halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O— when one or both are present more than once Independently selected from carboxy, sulfonamide, amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino , Aminoalkyl, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₂ is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl;
Any methylene group in the o, p, and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. ; And
S, T, U, and V are carbon or nitrogen, provided that at least one of S, T, U, and V is nitrogen and S, T, U, or V is nitrogen If no substituent is present on the nitrogen,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IIIc

According to claim 29 or 37, and pharmaceutically acceptable salts and solvates thereof, in formula IIIc:
Y and R ₆ are as defined in claim 37;
Y ₂ , o, p, and q are as defined in claim 29;
R ₁ and R ₅ , when one or both are present more than once, are each independently halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalo Selected from methyl, C-carboxy, O-carboxy, sulfonamido, amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amido, amino, aminoalkyl, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino; and
The methylene group in either the o region, the p region, and the q region, or Y ₂ is independently C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl as required. Has been replaced,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Formula IV

And the pharmaceutically acceptable salts and solvates thereof, in formula IV:
Y is phenyl, 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl, where any ring carbon is independently halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C Optionally substituted with -amide, N-amide, C-carboxy, O-carboxy, sulfonamido, amino, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl;
Y ₁ is a divalent carbocycle, divalent heterocycle, divalent phenyl or divalent heteroaryl, wherein any ring atom is independently halo, C _1-5 alkyl, nitro, Optionally substituted with cyano, trihalomethyl, C _1-5 alkoxy, C-amide, N-amide, sulfonamido, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl, or
Y ₁ is C _2-8 alkylene or C _2-8 alkenylene, and optionally -O-, -S-, -S (= O)-, -S (= O) _2- , -OC (= O) N (R)-, -N (R) C (= O) O-, -C (= O) N (R)-, -N (R) C (= O)-, -N ( R) C (= O) N (R)-, -N (R)-, -C (= O)-, -OC (= O)-, -C (= O) O-, -OS (= O ) ₂ N (R)-, -N (R) S (= O) ₂ O-, -SC (= O)-, -C (= O) S-, -OC (= S) N (R)- , -N (R) C (= S) O-, -C (= S) N (R)-, -N (R) C (= S)-, -N (R) C (= S) N ( R)-, -C (= S)-, -OC (= S)-, -C (= S) O-, -S (= O) ₂ N (R)-, -N (R) S (= O) _2- , -S (= O) ₂ N (R) C (= O)-, or -C (= O) N (R) S (= O) _2- once, twice, or 3 Intervening times;
Where in Y ₁ , R is H, halo, C _1-4 alkyl, C _1-4 alkenyl, or C _1-4 alkynyl;
Y _{2 is, -OCH 2 -, - SCH 2} -, - N (R) CH 2 -, - N (R) C (= O) -, - C (= O) N (R) -, - S ( = O) ₂ CH _2- , -S (= O) CH _2- , -CH ₂ O-, -CH ₂ CH ₂ O-, -CH ₂ S-, -CH ₂ N (R)-, -CH ₂ S (= O) _2- , -CH ₂ S (= O)-, -C (= O) O-, -OC (= O)-, -SO ₂ N (R)-, -N (R) SO _2- , ethylene, propylene, n-butylene, -OC _1-4 alkylene-N (R) C (= O)-, -OC _1-4 alkylene-C (= O) N (R)-, -N ( R) C (= O) -C _1-4 alkylene-O-, -C (= O) N (R) -C _1-4 alkylene-O-, -C _1-4 alkylene-S (= O) ₂ -, -C _1-4 alkylene-S (= O)-, -S (= O) ₂ -C _1-4 alkylene-, -S (= O) -C _1-4 alkylene-, -C _1-4 alkylene _{-SO 2 N (R) -,} - C 1~4 alkylene _{-N (R) SO 2 -,} - SO 2 N (R) -C 1~4 alkylene -, - N (R) SO 2 -C 1 _{to 4} alkylene -, - C _{1 to 4} alkylene -OC _{1 to 4} alkylene -, - OC _{1 to 4} alkylene -, - C _{1 to 4} alkylene -O _-, - SC _1~4 alkylene -, - C _{1 to 4} alkylene -S _-, - C _1~4 alkylene -SC _{1 to 4} alkylene -, - N (R) -C 1~4 alkylene -, - C _{1 to 4} alkylene -N (R) -, - C 1~4 alkylene -N (R) -C _1~4 alkylene -, - C _{1 to 4} alkylene -C (= O) -OC _1~4 alkylene _-, - C 1~ ₄ alkylene-OC (= O) -C _1-4 alkylene-, -C _1-4 alkylene-C (= O) -N (R) -C _1-4 alkylene-, -C _1-4 alkylene-N ( R) -C (= O) -C _1-4 alkylene-, -C (= O) -N (R) -C _1-4 alkylene-SO ₂ N (R)-, or -N (R) -C (= O) -C _1-4 alkylene-SO ₂ N (R)-;
Where in Y ₂ R is H, C _1-5 alkyl, C _1-5 alkenyl, C _1-5 alkynyl or a 5- or 6-membered heterocycle together with the carbon atom of Y ₃ Methylene or ethylene to form;
Y ₃ is aryl or heteroaryl, wherein any ring carbon is independently halo, C _1-5 alkyl, nitro, cyano, trihalomethyl, C _1-5 alkoxy, C-amide, N-amide , Sulfonamide, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl, optionally substituted, where C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide , Amino, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
Y ₄ is optionally present and, when present, is an aryl, heteroaryl, carbocycle, or heterocycle, wherein any ring atom is independently halo, C _1-5 alkyl, nitro , Cyano, trihalomethyl, C _1-5 alkoxy, C-amide, N-amide, sulfonamido, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, sulfinyl, optionally substituted, where C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
o, p, and q are each independently 0, 1, or 2;
o region, p region, and q region, and any alkylene or alkenylene group Y ₂ is unsubstituted C _{1 to 4} alkyl, halo, unsubstituted C _{1 to 4} haloalkyl or unsubstituted C ₃ or C ₄ cycloalkyl, Optionally substituted with alkyl;
Provided that when Y ₁ is divalent phenyl, q is 0, and p is 1, Y ₄ is present;
Provided that when Y ₁ is C _2-8 alkylene and q is 0, Y ₄ is present; and
2-cyano-1-[[4-[(4-phenylphenyl) sulfonylamino] phenyl] methyl] -3- (4-pyridyl) guanidine compounds, and pharmaceutically acceptable salts and solvates thereof object. Said structure is of formula IVa

According to claim 50, and pharmaceutically acceptable salts and solvates thereof, according to formula IVa:
Y is 3-pyridinyl or 4-pyridinyl, optionally substituted as defined for Y for formula I;
Y ₂ , Y ₃ , Y ₄ , and q are as defined in claim 50;
n is 3, 4, 5, 6, or 7; and
Any methylene group in Y ₂ and the n and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IVa1

According to claim 50 or 51, and pharmaceutically acceptable salts and solvates thereof, in formula IVa1:
Y is as defined in claim 51;
Y ₃ , Y ₄ , and q are as defined in claim 50;
n is 3, 4, 5, 6, or 7;
any methylene group in the n and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl; and
R ₃ and R ₄ are each independently H, halo, or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which they are both attached, is cyclopropyl Forming a ring or cyclobutyl ring,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IVa3

53. A compound according to any one of claims 50 to 52, and pharmaceutically acceptable salts and solvates thereof, according to formula IVa3:
Y is as defined in claim 51;
Y ₄ and q are as defined in claim 50;
n is 3, 4, 5, 6, or 7;
any methylene group in the n and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino; and
R ₃ and R ₄ are each independently H, halo, or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which they are both attached, is cyclopropyl Forming a ring or cyclobutyl ring,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IVa5

54. A compound according to any one of claims 50 to 53, and pharmaceutically acceptable salts and solvates thereof, according to formula IVa5:
Y is as defined in claim 51;
q is as defined in claim 50;
n is 3, 4, 5, 6, or 7;
any methylene group in the n and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₁ and R ₅ , when one or both are present more than once, are each independently halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalo Selected from methyl, C-carboxy, O-carboxy, sulfonamido, amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amido, amino, aminoalkyl, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino; and
R ₃ and R ₄ are each independently H, halo, or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which they are both attached, is cyclopropyl Forming a ring or cyclobutyl ring,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IVa2

According to claim 50 or 51, and pharmaceutically acceptable salts and solvates thereof, in formula IVa2:
Y is as defined in claim 51;
Y ₃ , Y ₄ , and q are as defined in claim 50;
n is 3, 4, 5, 6, or 7;
any methylene group in the n and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl; and
R ₂ is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IVa4

According to claim 50, 51, or 55, and pharmaceutically acceptable salts and solvates thereof, in formula IVa4:
Y is as defined in claim 51;
Y ₄ and q are as defined in claim 50;
n is 3, 4, 5, 6, or 7;
any methylene group in the n and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino; and
R ₂ is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IVa6

According to claim 50, 51, 55, or 56, and pharmaceutically acceptable salts and solvates thereof, in Formula IVa6:
Y is as defined in claim 51;
q is as defined in claim 50;
n is 3, 4, 5, 6, or 7;
any methylene group in the n and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino; and
R ₂ is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IVb

According to claim 50, and pharmaceutically acceptable salts and solvates thereof, according to formula IVb:
Y is 3-pyridinyl or 4-pyridinyl, optionally substituted as defined for Y for formula I;
o, p, q, Y ₂ , Y ₃ , and Y ₄ are as defined in claim 50;
o, p, and q regions and any methylene group in Y ₂ are independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. Have been;
R ₆ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide Independently selected from, amino, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl;
Where S, T, U, and V are carbon or nitrogen, provided that when S, T, U, or V is nitrogen, there are no substituents on the nitrogen;
Provided that when q is 0, S, T, U, and V are carbon and p is 1, Y ₄ is present; and
2-cyano-1-[[4-[(4-phenylphenyl) sulfonylamino] phenyl] methyl] -3- (4-pyridyl) guanidine compounds, and pharmaceutically acceptable salts and solvates thereof object. Said structure is of formula IVb1

According to claim 50 or 58, and pharmaceutically acceptable salts and solvates thereof, in formula IVb1:
Y and R ₆ are as defined in claim 58;
o, p, q, Y ₃ and Y ₄ are as defined in claim 50;
Any methylene group in the o, p, and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. ; And
R ₃ and R ₄ are each independently H, halo, or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which they are both attached, is cyclopropyl Forming a ring or cyclobutyl ring,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IVb3

According to claim 50, 58, or 59, and pharmaceutically acceptable salts and solvates thereof, in formula IVb3:
Y and R ₆ are as defined in claim 58;
o, p, q, and Y ₄ are as defined in claim 50;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₃ and R ₄ are each independently H, halo, or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which both are attached, is cyclopropyl Forming a ring or a cyclobutyl ring; and
Any methylene group in the o, p, and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. ,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IVb5

A compound according to claim 50 or any one of claims 58-60, and pharmaceutically acceptable salts and solvates thereof, according to formula IVb5:
Y and R ₆ are as defined in claim 58;
o, p, and q are as defined in claim 50;
R ₁ and R ₅ , when one or both are present more than once, are each independently halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalo Selected from methyl, C-carboxy, O-carboxy, sulfonamido, amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amido, amino, aminoalkyl, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₃ and R ₄ are each independently H, halo, or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which both are attached, is cyclopropyl Forming a ring or a cyclobutyl ring; and
Any methylene group in the o, p, and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. ,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IVb2

According to claim 50 or 58, and pharmaceutically acceptable salts and solvates thereof, in formula IVb2:
Y and R ₆ are as defined in claim 58;
o, p, q, Y ₃ and Y ₄ are as defined in claim 50;
Any methylene group in the o, p, and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. ;
R ₂ is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl; and the compound is:
2-cyano-1-[[4-[(4-phenylphenyl) sulfonylamino] phenyl] methyl] -3- (4-pyridyl) guanidine compounds, and pharmaceutically acceptable salts and solvates thereof object. Said structure is of formula IVb4

According to claim 50, 58, or 62, and pharmaceutically acceptable salts and solvates thereof, in Formula IVb4:
Y and R ₆ are as defined in claim 58;
o, p, q, and Y ₄ are as defined in claim 50;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₂ is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl;
Any methylene group in the o, p, and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. ,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IVb6

According to claim 50, 58, 62, or 63, and pharmaceutically acceptable salts and solvates thereof, in Formula IVb6:
Y and R ₆ are as defined in claim 58;
o, p, and q are as defined in claim 50;
R ₁ and R ₅ , when one or both are present more than once, are each independently halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalo Selected from methyl, C-carboxy, O-carboxy, sulfonamido, amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amido, amino, aminoalkyl, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₂ is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl; and
Any methylene group in the o, p, and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. ,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IVb7

According to claim 50 or 58, and pharmaceutically acceptable salts and solvates thereof, in formula IVb7:
Y and R ₆ are as defined in claim 51;
o, p, and q are as defined in claim 50;
R ₁ and R ₅ , when one or both are present more than once, are each independently halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalo Selected from methyl, C-carboxy, O-carboxy, sulfonamido, amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amido, amino, aminoalkyl, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₃ and R ₄ are each independently H, halo, or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon to which they are both attached, is cyclopropyl Forming a ring or a cyclobutyl ring;
Any methylene group in the o, p, and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. ; And
S, T, U, and V are carbon or nitrogen, provided that at least one of S, T, U, and V is nitrogen and S, T, U, or V is nitrogen If no substituent is present on the nitrogen,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IVb8

According to claim 50 or 58, and pharmaceutically acceptable salts and solvates thereof, in formula IVb8:
Y and R ₆ are as defined in claim 58;
o, p, and q are as defined in claim 50;
R ₁ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide , Amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, And alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₂ is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl;
Any methylene group in the o, p, and q regions is independently optionally substituted with C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl. ; And
S, T, U, and V are carbon or nitrogen, provided that at least one of S, T, U, and V is nitrogen and S, T, U, or V is nitrogen If no substituent is present on the nitrogen,
Compounds, and pharmaceutically acceptable salts and solvates thereof. Said structure is of formula IVc

According to claim 50 or 58, and pharmaceutically acceptable salts and solvates thereof, in formula IVc:
Y is 3-pyridinyl or 4-pyridinyl, optionally substituted as defined for Y for formula I;
Y ₂ , o, p, and q are as defined in claim 50;
R ₁ and R ₅ , when one or both are present more than once, are each independently halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalo Selected from methyl, C-carboxy, O-carboxy, sulfonamido, amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amido, amino, aminoalkyl, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R ₆ when present more than once, halo, C _1-5 alkyl, nitro, cyano, C _1-5 alkoxy, C-amide, N-amide, trihalomethyl, C-carboxy, O-carboxy, sulfonamide Independently selected from, amino, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl; and
o-region, p-region, and q-region, or any methylene group in Y ₂ is independently C _1-4 alkyl, halo, C _1-4 haloalkyl, or C ₃ or C ₄ cycloalkyl as required And if Y ₂ is —C (═O) N (H) —, then Y ₄ is present,
Compounds, and pharmaceutically acceptable salts and solvates thereof.   51. The compound of any one of claims 1, 11, 29, and 50, wherein Y is phenyl.   51. The compound of any one of claims 1, 11, 29, and 50, wherein Y is 2-pyridinyl.   68. The compound of any one of claims 1, 11, and 29-67, wherein Y is 3-pyridinyl.   68. The compound of any one of claims 1, 11, and 29-67, wherein Y is 4-pyridinyl.   Claims 1, 11, 29, 50, and 68 wherein Y is not substituted or is substituted once, twice, three times, or four times as defined for Y in claim 1 72. A compound according to any one of -71.   The optional substituents for Y are halo (e.g., fluoro, etc.), methyl, nitro, cyano, trihalomethyl, methoxy, amino, hydroxyl, or mercapto, 1, 1, 29, 50, and 68-72. The compound of any one of these. Y is either unsubstituted 3-pyridinyl, or is 3-pyridinyl substituted with NH ₂ at the 4-position, compound according to any one of claims 1,11,29～67, and 70.   75. The compound according to any one of claims 29 to 67, and 70 to 74, wherein q is 0.   75. The compound according to any one of claims 29 to 67, and 70 to 74, wherein q is 1.   75. The compound according to any one of claims 29 to 67, and 70 to 74, wherein q is 2.   78. The compound of any one of claims 29 to 67, 70 to 74, 76, and 77, wherein any methylene group in the q region is optionally substituted with fluoro or methyl.   78. The compound of any one of claims 29 to 67, 70 to 74, 76, and 77, wherein any methylene group in the q region is all fully saturated.   80. The compound of any one of claims 29, 37-50, 58-67, and 70-79, wherein p is 0.   80. The compound of any one of claims 29, 37-50, 58-67, and 70-79, wherein p is 1.   80. The compound of any one of claims 29, 37-50, 58-67, and 70-79, wherein p is 2.   83. Any one of claims 29, 37-50, 58-67, 70-79, 81, and 82, wherein any methylene group in the p region is optionally substituted with fluoro or methyl. Compound.   89. The compound of any one of claims 29, 37-50, 58-67, 70-79, 81, and 82, wherein any methylene groups in the p region are all fully saturated. R is, in Y _1, is hydrogen, A compound according to any one of claims 1,11,29,50, and 68 to 84. Y ₁ is a divalent carbocycle, divalent heterocycle, divalent phenyl or divalent heteroaryl, wherein any ring carbon atom is independently halo, C _1-5 alkyl, nitro , cyano, trihalomethyl, C _{1 to 5} alkoxy, C-amido, N- amido, sulfonamido, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, and optionally substituted with a sulfonyl or sulfinyl, claim 85. A compound according to any one of 1, 9-11, 25-29, 50, and 68-84. Y ₁ is divalent cyclohexyl, divalent piperidinyl, divalent phenyl, divalent pyridinyl, divalent pyrimidinyl, divalent thiophenyl, and divalent triazolyl, where any ring carbon atom is Independently, halo, C _1-5 alkyl, nitro, cyano, trihalomethyl, C _1-5 alkoxy, C-amide, N-amide, sulfonamido, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, or 95. The compound of any one of claims 1, 9-11, 25-29, 50, and 68-86, optionally further substituted with sulfinyl. Or R ₆ is absent or 1, 2, 3, or present 4 times, any one of claims 5～8,17～24,37～49,58～67, and 70-84 Compound described in 1. Or R ₆ is absent, or fluoro, methyl or trifluoromethyl, according to any one of claims 5～8,17～24,37～49,58～67,70～84, and 88 Compound. R ₆ is absent, A compound according to any one of claims 5～8,17～24,37～49,58～67,70～84,88, and 89.   95. The compound of any one of claims 5, 17, 37, 47-49, 58, 65-67, 70-84, and 88-90, wherein only S is nitrogen.   95. The compound of any one of claims 5, 17, 37, 47-49, 58, 65-67, 70-84, and 88-90, wherein only T is nitrogen.   95. The compound of any one of claims 5, 17, 37, 47-49, 58, 65-67, 70-84, and 88-90, wherein only U is nitrogen.   95. The compound of any one of claims 5, 17, 37, 47-49, 58, 65-67, 70-84, and 88-90, wherein only V is nitrogen.   90. In any one of claims 5, 17, 37, 47-49, 58, 65-67, 70-84, and 88-90, wherein at least two of S, T, U, and V are nitrogen. The described compound.   96. The compound of any one of claims 5, 17, 37, 47-49, 58, 65-67, 70-84, 88-90, and 95, wherein T and V are nitrogen.   96. The compound of any one of claims 5, 17, 37, 47-49, 58, 65-67, 70-84, 88-90, and 95, wherein S and U are nitrogen.   85. The compound according to any one of claims 2-4, 12-16, 30-36, 51-57, and 70-84, wherein n is 4, 5, or 6.   99. The compound of any one of claims 2-4, 12-16, 30-36, 51-57, 70-84, and 98, wherein n is 4.   99. The compound of any one of claims 2-4, 12-16, 30-36, 51-57 and 70-84, and 98, wherein n is 5.   99. The compound of any one of claims 2-4, 12-16, 30-36, 51-57 and 70-84, and 98, wherein n is 6.   Any of the n-regions, wherein any methylene group is optionally substituted with fluoro or methyl, any of claims 2-4, 12-16, 30-36, 51-57, 70-84, and 98-101 2. The compound according to item 1.   102. The compound of any one of claims 2-4, 12-16, 30-36, 51-57, 70-84, and 98-101, wherein any methylene groups in the n region are all fully saturated.   98. The compound of any one of claims 29, 37-50, 58-67, 70-84, and 88-97, wherein o is 0.   98. The compound of any one of claims 29, 37-50, 58-67, and 70-97, wherein o is 1.   98. The compound of any one of claims 29, 37-50, 58-67, and 70-97, wherein o is 2.   107. Any methylene group in the o region is optionally substituted with fluoro or methyl, according to any one of claims 29, 37-50, 58-67, 70-97, 105, and 106. Compound.   107. The compound of any one of claims 29, 37-50, 58-67, 70-97, 105, and 106, wherein any methylene groups in the o region are all fully saturated. Y _{2 is, -OCH 2 -, - SCH 2} -, - N (R) CH 2 -, - CH 2 O -, - CH 2 S -, - CH 2 N (R) -, - SO 2 N (R )-, -N (R) SO _2- , -C _1-4 alkylene-SO ₂ N (R)-, -C _1-4 alkylene-N (R) SO _2- , -SO ₂ N (R)- C _{1 to 4} alkylene -, - N (R) SO 2 -C 1~4 alkylene -, - C _{1 to 4} alkylene -OC _{1 to 4} alkylene -, - OC _{1 to 4} alkylene -, - C _{1 to 4} alkylene -O -, - SC _{1 to 4} alkylene -, - C _{1 to 4} alkylene -S -, - C _{1 to 4} alkylene -SC _{1 to 4} alkylene -, - N (R) -C 1~4 alkylene -, - C _1-4 alkylene-N (R)-, or -C _1-4 alkylene-N (R) -C _1-4 alkylene-, where R is H, halo, C _1-5 alkyl, C 1. Any one of claims 1, 2, ₅ , 11, 12, 17, 24, 29, 30, 37, 49 to 51, 58, and 67 to 108, which is _1-5 alkenyl or C _1-5 alkynyl. The compound according to item. Y _{2 is, -S (= O) 2 CH} 2 -, - S (= O) CH 2 -, - CH 2 O -, - CH 2 S -, - CH 2 N (R) -, - CH 2 S (= O) _2- , -CH ₂ S (= O)-, -C (= O) O-, -OC (= O)-, -SO ₂ N (R)-, -N (R) SO ₂ -, -OC _1-4 alkylene-N (R) C (= O)-, -C _1-4 alkylene-S (= O) _2- , -C _1-4 alkylene-S (= O)-,- S (= O) ₂ -C _1-4 alkylene-, -S (= O) -C _1-4 alkylene-, -C _1-4 alkylene-SO ₂ N (R)-, -C _1-4 alkylene- N (R) SO _2- , -SO ₂ N (R) -C _1-4 alkylene-, -N (R) SO ₂ -C _1-4 alkylene-, -C _1-4 alkylene-OC _1-4 alkylene -, - OC _{1 to 4} alkylene -, - C _{1 to 4} alkylene -O _-, - C _1~4 alkylene -S _-, - C _1~4 alkylene -SC _{1 to 4} alkylene -, - C _{1 to 4} alkylene -N (R)-, -C _1-4 alkylene-N (R) -C _1-4 alkylene-, -C _1-4 alkylene-C (= O) -OC _1-4 alkylene-, -C _{1- 4} alkylene-OC (= O) -C _1-4 alkylene-, -C _1-4 alkylene-C (= O) -N (R) -C _1-4 alkylene-, or -C _1-4 alkylene-N (R) -C (= O) -C _1-4 alkylene- Wherein R is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl, 29, 32, 29, 12, 17, 24, 29 , 30, 37, 49-51, 58, and 67-108. Y ₂ is -SCH ₂ - is, according to any one of claims 1,2,5,11,12,17,24,29,30,37,49～51,58, and 67-108 Compound. Y ₁ is --N (R) CH _2- , wherein R is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl. 111. A compound according to any one of 5, 11, 12, 17, 24, 29, 30, 37, 49-51, 58, and 67-108. Y ₂ is -N (R) C (= O)-, wherein R is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl. , 2, 5, 11, 12, 17, 24, 29, 30, 37, 49-51, 58, and 67-108. Y ₂ is -C (= O) N (R)-, wherein R is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl. , 2, 5, 11, 12, 17, 24, 29, 30, 37, 49-51, 58, and 67-108. Any of claims 1, ₂ , 5, 11, 12, 17, 24, 29, 30, 37, 49-51, 58, and 67-108, wherein Y ₂ is -S (= O) ₂ CH 2-. 2. The compound according to item 1. Any one of claims 1, ₂ , 5, 11, 12, 17, 24, 29, 30, 37, 49-51, 58, and 67-108, wherein Y ₂ is -S (= O) CH _2- . The compound according to item 1. Y ₂ is -CH ₂ S-, according to any one of claims 1,2,5,11,12,17,24,29,30,37,49～51,58, and 67-108 Compound. Y ₁ is --CH ₂ N (R)-, wherein R is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl. 111. A compound according to any one of 5, 11, 12, 17, 24, 29, 30, 37, 49-51, 58, and 67-108. Any of claims 1, ₂ , 5, 11, 12, 17, 24, 29, 30, 37, 49-51, 58, and 67-108, wherein Y ₂ is -CH ₂ S (= O) 2-. 2. The compound according to item 1. Y ₂ is -CH ₂ S (= O) - is, any one of claims 1,2,5,11,12,17,24,29,30,37,49～51,58, and 67-108 The compound according to item 1. 1. Any one of claims 1, 2, 5, 11, 12, 17, 24, 29, 30, 37, 49 to 51, 58, and 67 to 108, wherein Y ₂ is —C (═O) O—. The compound according to item. Y ₂ is -OC (= O) - is any one of claims 1,2,5,11,12,17,24,29,30,37,49～51,58, and 67-108 Compound described in 1. Y ₁ is --N (R) SO _2- , wherein R is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl. 111. A compound according to any one of 5, 11, 12, 17, 24, 29, 30, 37, 49-51, 58, and 67-108. Y ₂ is ethylene, a compound according to any one of claims 1,2,5,11,12,17,24,29,30,37,49～51,58, and 67-108. Y ₂ is propylene, A compound according to any one of claims 1,2,5,11,12,17,24,29,30,37,49～51,58, and 67-108. Y ₂ is n- butylene, compound according to any one of claims 1,2,5,11,12,17,24,29,30,37,49～51,58, and 67-108 . Y ₂ is —OC _1-4 alkylene-N (R) C (═O) —, wherein R is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl. 109. The compound of any one of claims 1, 2, 5, 11, 12, 17, 24, 29, 30, 37, 49-51, 58, and 67-108. Y ₂ is —OC _1-4 alkylene-C (═O) N (R) —, wherein R is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl. 109. The compound of any one of claims 1, 2, 5, 11, 12, 17, 24, 29, 30, 37, 49-51, 58, and 67-108. Y ₂ is —N (R) C (═O) —C _1-4 alkylene-O—, wherein R is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1- 109. The compound of any one of claims 1, 2, ₅ , 11, 12, 17, 24, 29, 30, 37, 49-51, 58, and 67-108, which is ₅ alkynyl. Y ₂ is —C (═O) N (R) —C _1-4 alkylene-O—, wherein R is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1- 109. The compound of any one of claims 1, 2, ₅ , 11, 12, 17, 24, 29, 30, 37, 49-51, 58, and 67-108, which is ₅ alkynyl. Claims 1, ₂ , 5, 11, 12, 17, 24, 29, 30, 37, 49-51, 58, and 67 wherein Y ₂ is -C _1-4 alkylene-S (= O) _2-. 110. The compound according to any one of -108. Claims 1, 2, 5, 11, 12, 17, 24, 29, 30, 37, 49-51, 58, and 67-- wherein Y ₂ is -C _1-4 alkylene-S (= O)-. 109. The compound according to any one of 108. Claims 1, 2, 5, 11, 12, 17, 24, 29, 30, 37, 49-51, 58, and 67, wherein Y ₂ is -S (= O) ₂ -C _1-4 alkylene-. 110. The compound according to any one of -108. Claims 1, 2, 5, 11, 12, 17, 24, 29, 30, 37, 49-51, 58, and 67-, wherein Y ₂ is -S (= O) -C _1-4 alkylene-. 109. The compound according to any one of 108. Y ₂ is —C _1-4 alkylene-SO ₂ N (R) —, wherein R is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl. 109. A compound according to any one of claims 1, 2, 5, 11, 12, 17, 24, 29, 30, 37, 49-51, 58, and 67-108. Y ₂ is —C _1-4 alkylene-N (R) SO ₂ —, wherein R is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl. 109. A compound according to any one of claims 1, 2, 5, 11, 12, 17, 24, 29, 30, 37, 49-51, 58, and 67-108. Y ₂ is —SO ₂ N (R) —C _1-4 alkylene-, wherein R is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl. 109. A compound according to any one of claims 1, 2, 5, 11, 12, 17, 24, 29, 30, 37, 49-51, 58, and 67-108. Y ₂ is —N (R) SO ₂ —C _1-4 alkylene-, wherein R is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 alkynyl, 109. A compound according to any one of claims 1, 2, 5, 11, 12, 17, 24, 29, 30, 37, 49-51, 58, and 67-108. Claims 1, 2, 5, 11, 12, 17, 24, 29, 30, 37, 49-51, 58, and 67-, wherein Y ₂ is -C _1-4 alkylene-OC _1-4 alkylene-. 109. The compound according to any one of 108. Y ₂ is -OC _{1 to 4} alkylene - is any one of claims 1,2,5,11,12,17,24,29,30,37,49～51,58, and 67-108 Compound described in 1. Any one of claims 1, 2, 5, 11, 12, 17, 24, 29, 30, 37, 49-51, 58, and 67-108, wherein Y ₂ is -C _1-4 alkylene-O-. The compound according to item 1. Y ₂ is -SC _{1 to 4} alkylene - is any one of claims 1,2,5,11,12,17,24,29,30,37,49～51,58, and 67-108 Compound described in 1. Any one of claims 1, 2, 5, 11, 12, 17, 24, 29, 30, 37, 49-51, 58, and 67-108, wherein Y ₂ is -C _1-4 alkylene-S-. 2. The compound according to item 1. Claims 1, 2, 5, 11, 12, 17, 24, 29, 30, 37, 49-51, 58, and 67-- wherein Y ₂ is -C _1-4 alkylene-SC _1-4 alkylene-. 109. The compound according to any one of 108. Y ₂ is -N (R) -C _{1 to 4} alkylene -, and wherein R is H, halo, C _{1 to 5} alkyl, C _{1 to 5} alkenyl or C _{1 to 5} alkynyl, claim 110. The compound of any one of 1, 2, 5, 11, 12, 17, 24, 29, 30, 37, 49-51, 58, and 67-108. Y ₂ is -C _{1 to 4} alkylene -N (R) -, wherein R is H, halo, C _{1 to 5} alkyl, C _{1 to 5} alkenyl or C _{1 to 5} alkynyl, claim 110. The compound of any one of 1, 2, 5, 11, 12, 17, 24, 29, 30, 37, 49-51, 58, and 67-108. Y ₂ is —C _1-4 alkylene-N (R) —C _1-4 alkylene-, wherein R is H, halo, C _1-5 alkyl, C _1-5 alkenyl, or C _1-5 109. The compound of any one of claims 1, 2, 5, 11, 12, 17, 24, 29, 30, 37, 49-51, 58, and 67-108, which is alkynyl. Claims 1, 2, 5, 11, 12, 17, 24, 29, 30, 37, 49-51, wherein Y ₂ is -C _1-4 alkylene-C (= O) -OC _1-4 alkylene-. , 58, and 67-108. Y ₁ is -C _1-4 alkylene-OC (= O) -C _1-4 alkylene-, claim 1, 2, 5, 11, 12, 17, 24, 29, 30, 37, 49-51 , 58, and 67-108. Y ₂ is -C _1-4 alkylene-C (= O) -N (R) -C _1-4 alkylene-, where R is H, halo, C _1-5 alkyl, C _1-5 alkenyl. Or C _1-5 alkynyl according to any one of claims 1, 2, ₅ , 11, 12, 17, 24, 29, 30, 37, 49-51, 58, and 67-108. Compound. Y ₂ is —C _1-4 alkylene-N (R) —C (═O) —C _1-4 alkylene-, where R is H, halo, C _1-5 alkyl, C _1-5 alkenyl. Or C _1-5 alkynyl according to any one of claims 1, 2, ₅ , 11, 12, 17, 24, 29, 30, 37, 49-51, 58, and 67-108. Compound. R is, in Y _2, is hydrogen, A compound according to any one of claims 1,11,29,50, and 68 to 151. R ₂ is hydrogen or cyclopropyl, claim 4,7,10,15,16,20,21,27,28,34～36,41～43,48,55～57,62～64,66, And the compound according to any one of 70 to 108. R ₂ is hydrogen, claim 4,7,10,15,16,20,21,27,28,34～36,41～43,48,55～57,62～64,66,70～108 , And the compound according to any one of 153. Or both R ₃ and R ₄ are hydrogen, or both, is fluoro claim 6,9,18,19,25,26,31～33,38～40,43,46,47,49 , 52-54, 59-61, 65, and 70-108. Both R ₃ and R ₄ are hydrogen, claim 6,9,18,19,25,26,31～33,38～40,43,46,47,49,52～54,59～61 , 65, 70 to 108, and 155.   99. The compound of any one of claims 8, 22, 23, 29-46, and 70-108, wherein u is 0.   99. The compound of any one of claims 8, 22, 23, 29-46, and 70-1008, wherein u is 1.   99. The compound of any one of claims 8, 22, 23, 29-46, and 70-1008, wherein u is 1 and the methylene group in the u region is substituted with fluoro or methyl.   99. The compound of any one of claims 8, 22, 23, 29-46, and 70-1008, wherein u is 1 and the methylene group in the u region is fully saturated. Y ₃ is phenyl, pyridinyl, pyrimidinyl, divalent phenyl, divalent pyridinyl, or divalent pyrimidinyl, wherein any ring carbon is independently halo, C _1-5 alkyl, nitro, cyano , Trihalomethyl, C _1-5 alkoxy, C-amide, N-amide, sulfonamido, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl, and optionally substituted In the case of a ring independently, halo, C _1-5 alkyl, nitro, cyano, trihalomethyl, C _1-5 alkoxy, C-amide, N-amide, sulfonamido, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl or are further optionally substituted sulfinyl, where C _{1 to 5} alkyl, C _{1 to 5} a 12. Koxy, C-amide, N-amide, amino, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino, respectively, 11-13, 15, 17, 18, 20, 22 , 25, 27, 29-31, 34, 37, 38, 41, 44, 50-52, 55, 58, 59, 62, and 68-160. The optional substituents on Z and / or Y ₃ are selected such that Y ₃ is an electron-deficient aryl ring or an electron-deficient heteroaryl ring, and claim 11, 12, 15, 17, 20, 27, and The compound according to any one of 68 to 160. Z and / or R _1, the phenyl ring is selected to be electron-deficient compound according to any one of claims 16,21,28, and 68 to 160. Y ₄ is absent, and the optional substituents on Y ₃ is, Y ₃ is selected to be electron-deficient, claim 29,30,34,37,41,50,51,55,58 , 62, and 68-160. Y ₄ is optionally present and, when present, is an aryl, heteroaryl, carbocycle, or heterocycle, wherein any ring carbon atom is independently halo, C _1-5 alkyl, nitro, cyano, trihalomethyl, C _{1 to 5} alkoxy, C-amido, N- amido, sulfonamido, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, which is optionally substituted sulfinyl, where C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino. , 34, 35, 38, 39, 41, 42, 44, 45, 50-53, 55, 56, 58-60, 62, 63, and 68-164. Y ₄ is present, claim 29～32,34,35,38,39,41,42,44,45,50～53,55,56,58～60,62,63,68～164, and 165 The compound of any one of these. Y ₄ is phenyl, morpholino, piperazinyl, oxydiazolyl, oxazolyl, pyrrolidinyl, thienyl (thiophenyl), benzo [b] thienyl, naphtho [2,3-b] thienyl, thiantenyl, furyl (furanyl), isobenzofuranyl , Chromenyl, xanthenyl, phenoxathiinyl, pyrrolyl, 2H-pyrrolyl, pyrroline, imidazolyl, imidazolidinyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, Indolyl, indazolyl, purinyl, 4H-quinolidinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimi Nyl, phenanthrolinyl, phenazinyl, isothiazolyl, thiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, 1,4-dihydroquinoxaline-2,3-dione, 7-aminoisocoumarin, pyrido [1,2-a] pyrimidine -4-one, pyrazolo [1,5-a] pyrimidinyl, pyrazolo [1,5-a] pyrimidin-3-yl, 1,2-benzisoxazol-3-yl, benzimidazolyl, 2-oxoindolyl, 2 A group selected from -oxobenzimidazolyl, triazine, dioxolanyl, dithianyl, thiomorpholinyl, trithianyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclohexenyl, wherein each optional ring atom of the group is independently , halo, C _{1 to 5} alkyl, nitro, cyano, trihalomethyl, C _{1 to 5} alkoxy, Optionally substituted with C-amide, N-amide, sulfonamide, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, sulfinyl, where C _1-5 alkyl, C _1-5 alkoxy, C -Amide, N-amido, amino, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino, 29-32, 34, 35, 38, 39, 41, 42, 164. Compound according to any one of 44, 45, 50-53, 55, 56, 58-60, 62, 63, and 68-164. Y ₄ is a group selected from phenyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, pyrimidinyl, morpholino, piperazinyl, oxydiazolyl, oxazolyl, pyrrolidinyl, imidazolyl, and piperidinyl, each of the groups Any ring atom of is independently halo, C _1-5 alkyl, nitro, cyano, trihalomethyl, C _1-5 alkoxy, C-amide, N-amide, sulfonamido, amino, aminosulfonyl, hydroxyl, mercapto , Alkylthio, sulfonyl, sulfinyl, optionally substituted, wherein C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amido, amino, and alkylthio are each optionally Claims 29-32, 34, 35, 38, 39, 41, 42, 44, 45, substituted with heterocyclo, cycloalkyl, or amino 50～53,55,56,58～60,62,63, and A compound according to any one of 68 to 164. Y ₄ is:

Wherein V is N or C (H), and W is N, O, C (H), or S, wherein any ring atom is independently , halo, C _{1 to 5} alkyl, nitro, cyano, trihalomethyl, C _{1 to 5} alkoxy, C-amido, N- amido, sulfonamido, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, needs sulfinyl Optionally substituted, where C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino Claims 29-32, 34, 35, 38, 39, 41, 42, 44, 45, 50-53, 55, 56, 58-60, 62, 63, and 68-164 The compound according to item. R ₁ is absent or present once, twice, three times, or four times, claims 14, 16, 19, 21, 23, 24, 26, 28, 32, 33, 35, 36, 39 , 40, 42, 43, 45-49, 53-57, 60, 61, 63-67, 70-160, 163, and 165-169. R ₁ is present five times, the compound according to any one of claims 36,43,48,57,65,70～160,163, and 165-169. R ₁ is an electron withdrawing group, claim 14, 16, 19, 21, 23, 24, 26, 28, 32, 33, 35, 36, 39, 40, 42, 43, 45-49, 53, The compound according to any one of 54, 56, 60, 61, 63, 65, 67, 70 to 160, 163, and 165 to 170. R ₁ is halo, trihalomethyl, nitro, cyano, C-carboxy, O-carboxy, C-amide, and N-amide, wherein 14, 16, 19, 21, 23, 24, 26, 28, 32, 33, 35, 36, 39, 40, 42, 43, 45 to 49, 53, 54, 56, 60, 61, 63, 65, 67, 70 to 160, 163, and 165 to 172 The compound according to item. Y ₄ is absent, R ₁ is present 2 or 3 times, and each instance of R ₁ is an electron withdrawing group, and claims 35, 42, 56, 63, 70-160, 163, and The compound according to any one of 165 to 170. R ₁ is selected from C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, or alkylthio, each further substituted with heterocyclo, cycloalkyl, or amino Claims 14, 16, 19, 21, 23, 24, 26, 28, 32, 33, 35, 36, 39, 40, 42, 43, 45-49, 53, 54, 56, 60, 61, The compound according to any one of 63, 65, 67, 70 to 160, 163, and 165 to 170. Or R ₅ is absent, or 1, 2, 3, present 4 times, or 5 times, claim 33,40,43,46,47,49,54,61,65,67,70～ 174. A compound according to any one of 170, 172, and 173. R ₅ is selected from C _1-5 alkyl, C _1-5 alkoxy, C-amide, N-amide, amino, aminoalkyl, or alkylthio, each further substituted with heterocyclo, cycloalkyl, or amino 178. The compound of any one of claims 33, 40, 43, 46, 47, 49, 54, 61, 65, 67, 70-170, 172, 173, and 176. R ₁ is:

Where t is 0, 1, 2, 3, or 4, W is N (H), O, C (H) ₂ , or S, and R _a and R _b are Each independently hydro, C _3-6 cycloalkyl, or C _1-6 alkyl, or R _a and R _b together with a linking nitrogen atom between them, azetidine, pyrrolidine, or Forms piperidine, claim 14, 16, 19, 21, 23, 24, 26, 28, 32, 33, 35, 36, 39, 40, 42, 43, 45-49, 53, 54, 56, 60 , 61, 63, 65, 67, 70-160, 163, and 165-169. R ₅ is below:

Where t is 0, 1, 2, 3, or 4, W is N (H), O, C (H) ₂ , or S, and R _a and R _b are Each independently hydro, C _3-6 cycloalkyl, or C _1-6 alkyl, or R _a and R _b together with a linking nitrogen atom between them, azetidine, pyrrolidine, or 174. The compound of any one of claims 33, 40, 43, 46, 47, 49, 54, 61, 65, 67, 70-170, 172, and 173, which forms piperidine. R ₁ and / or R ₅ are present and the following:

Where R ₁ and R ₅ are each as follows:

Where t is 0, 1, 2, 3, or 4, W is N (H), O, C (H) ₂ , or S, and R _a and R _b are Each independently hydro, C _3-6 cycloalkyl, or C _1-6 alkyl, or R _a and R _b together with a linking nitrogen between them, azetidine, pyrrolidine, or piperidine Wherein R ₁ is C _1-4 haloalkyl or halo when both R ₁ and R ₅ are present on the biphenyl ring; 43, 40, 43, 46, 47, 49 , 54, 61, 65, 67, 70-170, 172, 173, and 175-178. Z ₀ is carbocycle, cycloalkyl, cycloalkenyl, heterocycle, heterocyclonoyl, aryl, heteroaryl, carbocycloalkyl, heterocyclylalkyl, arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, Or arylalkynyl, wherein each of the above groups is alkyl, alkylene, alkenyl, alkenylene, alkynyl, carbocycle, cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl, halo, hydro, hydroxyl, alkoxy, alkynyl Oxy, cycloalkyloxy, heterocyclooxy, aryloxy, heteroaryloxy, arylalkoxy, heteroarylalkoxy, mercapto, alkylthio, ali Ruthio, arylalkyl, heteroarylalkyl, heteroarylalkenyl, arylalkynyl, haloalkyl, aldehyde, thiocarbonyl, heterocyclonoyl, O-carboxy, C-carboxy, carboxylic acid, ester, C-carboxy salt, carboxyalkyl, carboxyalkenylene , Carboxyalkyl salt, carboxyalkoxy, carboxyalkoxyalkanoyl, amino, aminoalkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amide, N-amide, aminothiocarbonyl, hydroxyaminocarbonyl , Alkoxyaminocarbonyl, cyano, nitrile, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, sulfonamido, aminosulfoni , Amino sulfonyloxy, sulfonamido carbonyl, alkanoylamino sulfonyl, trihalomethyl sulfonyl or substituted at least once with trihalomethyl sulfonamide compound according to any one of claims 1 to 10 and 68 to 160. Z ₀ is, aryl optionally substituted, optionally substituted heteroaryl, carbocycle optionally substituted, is selected from heterocyclic ring optionally substituted, claim The compound according to any one of 1 to 10 and 68 to 160. Z ₀ is aryl, independently as required, optionally substituted alkyl, N-amide, optionally substituted carbocycle, optionally substituted carbocycloamino, required Optionally substituted heterocycle, optionally substituted heterocycloalkyl, optionally substituted heterocycloamino, optionally substituted heterocyclonoyl, optionally substituted aryl Optionally substituted heteroaryl, halo, hydro, hydroxyl, optionally substituted hydroxyalkyl, optionally substituted haloalkoxy, optionally substituted alkoxy, optionally Substituted aminoalkoxy, optionally substituted heterocycloalkoxy, optionally substituted haloalkyl, optionally substituted Amino, optionally substituted aminoalkyl, nitro, optionally substituted C-amide, optionally substituted N-amide, cyano, or optionally substituted sulfonamide 165. The compound of any one of claims 1-10 and 68-160, which is substituted one or more times. Z ₀ is a first aryl substituted with a second aryl, and each of the first aryl and the second aryl is independently an N-amide, an optionally substituted carbocycle , Carbocycloamino, optionally substituted heterocycle, heterocycloalkyl, heterocycloamino, heterocyclonoyl, halo, hydro, hydroxyl, hydroxyalkyl, haloalkoxy, alkoxy, aminoalkoxy, heterocycloalkoxy, haloalkyl, Optionally substituted one or more times with optionally substituted amino, aminoalkyl, nitro, optionally substituted C-amide, optionally substituted N-amide, cyano, or sulfonamide In some of such embodiments, the first aryl is phenyl, and In some of the forms, the second aryl is phenyl, and in some of such embodiments, both the first aryl and the second aryl are phenyl. Item 110. The compound according to any one of Items 1 to 10 and 68 to 160. Z ₀ is phenyl which is optionally substituted, an optionally substituted 2-pyridinyl, optionally substituted 3-pyridinyl, optionally substituted 4-pyridinyl, optionally Substituted pyrimidines, optionally substituted pyrazines, optionally substituted pyrazoles, optionally substituted thiophenes, optionally substituted ortho-biphenyls, optionally substituted 1-naphthalenyl, optionally substituted 2-naphthalenyl, optionally substituted quinazoline, optionally substituted benzothiadiazine, optionally substituted indole, and optionally 171. The compound of any one of claims 1-10 and 68-160, which is a substituted pyridopyrimidine.   Z is hydro, alkyl, N-amide, optionally substituted carbocycle, carbocycloamino, optionally substituted heterocycle, heterocycloalkyl, heterocycloamino, heterocyclonoyl, optionally Substituted aryl, optionally substituted heteroaryl, halo, hydro, hydroxyl, hydroxyalkyl, haloalkoxy, alkoxy, aminoalkoxy, heterocycloalkoxy, haloalkyl, optionally substituted amino, aminoalkyl 165, nitro, optionally substituted C-amide, optionally substituted N-amide, cyano, or sulfonamide according to any one of claims 11-28 and 68-163. Compound.   Z is hydro, optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrimidine, optionally substituted pyrazole, optionally substituted piperidine, Optionally substituted morpholine, optionally substituted piperazine, optionally substituted thiophene, optionally substituted imidazole, optionally substituted oxadiazole, optionally Optionally substituted oxazole, optionally substituted isoxazole, optionally substituted cyclohexyl, optionally substituted cyclohexylamino, optionally substituted piperidinylamino, or optionally 164. A compound according to any one of claims 11 to 28 and 68 to 163, which is an optionally substituted pyrrolidine.   68. A compound according to any one of claims 29 to 67, wherein Y is unsubstituted 3-pyridinyl and q is 1.   68. The compound of any one of claims 29, 37-50, and 58-67, wherein Y is unsubstituted 3-pyridinyl, q is 1, and p is 0.   68. The compound of any one of claims 29, 37-50, and 58-67, wherein Y is unsubstituted 3-pyridinyl, q is 1, p is 0, and o is 0. .   68. The compound of any one of claims 29, 37-50, and 58-67, wherein Y is unsubstituted 3-pyridinyl, q is 1, p is 0, and o is 0. . 68. Any of claims 29, 37-50, and 58-67, wherein Y is unsubstituted 3-pyridinyl, q is 1, p is 0, o is 0, and R ₆ is absent The compound according to item 1.   58. The compound of any one of claims 29-36 and 50-57, wherein Y is unsubstituted 3-pyridinyl, q is 1, and n is 4, 5, or 6.   Y is unsubstituted 3-pyridinyl, q is 1, n is 4, 5, or 6, and the methylene groups of n and q are all fully saturated. 58. The compound according to any one of 57. R ₆ and R ₇ is absent The compound according to any one of claims 5-8 and 17-24. Absent R ₆ and R _7, and an optional methylene group is fully saturated compound according to any one of claims 5-8 and 17-24. n is 4, 5 or 6, and no R _7, A compound according to any one of claims 2-4 and 12-16. n is 4, 5 or 6, there is no R _7, and any methylene group is fully saturated, the compounds according to any one of claims 2-4 and 12-16.   29. A compound according to any one of claims 1 to 28 wherein any methylene groups are all fully saturated.   A compound selected from Table 1, 2, 3, or 4.   200. A pharmaceutical composition comprising a compound according to any one of claims 1 to 200 and a pharmaceutically acceptable excipient.   200. A method of treating cancer comprising administering to a patient a therapeutically effective amount of a compound of any one of claims 1 to 200 or a pharmaceutical composition of claim 201. .   203. The method of claim 202, wherein the patient is a human patient.   204. The method of claim 202 or 203, further comprising identifying a patient in need of the treatment.   205. The method of any one of claims 202 to 204, further comprising administering a therapeutically effective amount of a PARP activator to the patient.   209. Any one of claims 202-205, wherein the PARP inhibitor is administered before, after, or simultaneously with the compound of any one of claims 1-200 or the pharmaceutical composition of claim 201. The method described in 1.   The PARP activator is an alkylating agent, methyl methanesulfonate (MMS), N-methyl-N′nitro-N-nitrosoguanidine (MNNG), nitrosourea, N-methyl-N-nitrosourea (MNU), streptozotocin , Carmustine, lomustine, nitrogen mustard, melphalan, cyclophosphamide, uramustine, ifosfamide, chlorambucil, mechlorethamine, alkylsulfonate, busulfan, platin, cisplatin, oxaliplatin, carboplatin, nedaplatin, satraplatin, triplatin tetranitrate, non Classical DNA alkylating agents, temozolomide, dacarbazine, mitozolomide, procarbazine, altretamine, radiation, X-rays, gamma rays, charged particles, UV, whole body or targeted radioisotope therapy, DNA damaging agents, topoisomerase inhibitors -, Camptothecin, β-lapachone, irinotecan, etoposide, anthracycline, doxorubicin, daunorubicin, epirubicin, idarubicin, valrubicin, mitozantrone, reactive oxygen generator, menadione, peroxynitrite, and antimetabolite, 5-FU, raltitrexed, 206. The method of claim 205, selected from pemetrexed, pralatrexate, methotrexate, gemcitabine, thioguanine, fludarabine, azathioprine, cytosine arabinoside, mercaptopurine, pentostatin, cladribine, folic acid, and floxuridine.   207. The method of any one of claims 202 to 207, wherein the cancer cell has a functional homologous recombination (HR) system.   208. The method of claim 208, further comprising confirming that the cells of the cancer have a functional HR system.   160. The method further comprising administering to the patient a therapeutically effective amount of a non-DNA damaging agent, wherein the non-DNA damaging agent is not a PARP activator and is also a compound of any one of claims 1-157. The method of any one of claims 202 to 209, which is not the pharmaceutical composition of item 201.   207. The method of any one of claims 202-204, further comprising administering a therapeutically effective amount of a PARP inhibitor to the patient.   The PARP inhibitor is selected from olaparib, AG014699 / PF-01367338, INO-1001, ABT-888, Iniparib, BSI-410, CEP-9722, MK4827, and E7016, or a combination thereof. the method of.   213. The method of any one of claims 202-204, 211, and 212, wherein the cancer does not have a functional homologous recombination (HR) system.   213. The method of claim 213, further comprising the step of confirming that the cells of the cancer do not have a functional HR system.   207. The method of any one of claims 202-204 and 210-214, further comprising administering to the patient a therapeutically effective amount of a DNA damaging agent, wherein the DNA damaging agent is other than a PARP inhibitor.   The DNA damaging agent is a DNA damaging agent, topoisomerase inhibitor, camptothecin, β-lapachone, irinotecan, etoposide, anthracycline, doxorubicin, daunorubicin, epirubicin, idarubicin, valrubicin, mitozantrone, reactive oxygen generator, menadione, peroxynitrite, And antimetabolite, 5-FU, raltitrexed, pemetrexed, pralatrexate, methotrexate, gemcitabine, thioguanine, fludarabine, azathioprine, cytosine arabinoside, mercaptopurine, pentostatin, cladribine, folic acid, and floxuridine 215. The method of claim 215.   213. The method of any one of claims 202-216, further comprising administering a therapeutically effective amount of a thymidylate synthase inhibitor to the patient.   218. The method of claim 217, wherein the thymidylate synthase inhibitor inhibits thymidylate synthase directly or indirectly.   227. The method of claim 217 or 218, wherein the thymidylate synthase inhibitor is selected from 5-FU, raltitrexed, and pemetrexed.   224. The method of any one of claims 202-219, wherein the cancer cells exhibit low levels of Naprtl expression.   223. The method of claim 220, further comprising administering to the patient nicotinic acid, or a compound capable of forming nicotinic acid in vivo.   223. The method of claim 221, wherein the compound or the pharmaceutical composition is administered at a dose that exceeds the maximum tolerated dose determined for monotherapy of the compound or the pharmaceutical composition.   223. The method of any one of claims 202-221, wherein the cancer overexpresses Nampt.   The cancer is Hodgkin's disease, non-Hodgkin lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, mantle cell leukemia, multiple myeloma, neuroblastoma, breast carcinoma, ovarian carcinoma, lung carcinoma, Wilms tumor, cervical carcinoma, testicular carcinoma, soft tissue sarcoma, primary macroglobulinemia, bladder carcinoma, chronic granulocytic leukemia, primary brain carcinoma, malignant melanoma, small cell lung carcinoma, gastric carcinoma, colon carcinoma, malignant Pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, head or neck carcinoma, osteogenic sarcoma, pancreatic carcinoma, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial carcinoma, polycythemia vera, essential thrombocytosis Diseases, adrenal cortical carcinoma, is selected from skin cancer, and prostate carcinoma, the method according to any one of claims 202-204.   Methods for treating cancer, systemic or chronic inflammation, rheumatoid arthritis, diabetes, obesity, T cell mediated autoimmune diseases, ischemia and other complications associated with these diseases and disorders in human patients 202. Identifying a patient in need of said treatment and administering a therapeutically effective amount of a compound according to any one of claims 1 to 200 or a pharmaceutical composition according to claim 201. Including the method.   One or more symptoms of cancer, systemic or chronic inflammation, rheumatoid arthritis, diabetes, obesity, T cell mediated autoimmune diseases, ischemia, and other complications associated with these diseases and disorders 200. A method of delaying development in a human patient or reducing its severity, the step of identifying a patient in need of said treatment, and a therapeutically effective amount of any one of claims 1-200. 200. A method comprising administering a compound according to claim 201 or a pharmaceutical composition according to claim 201.   202. Use of a compound according to any one of claims 1 to 200 or a pharmaceutical composition according to claim 201 for the manufacture of a medicament useful for human therapy.   Human treatment of cancer, systemic or chronic inflammation, rheumatoid arthritis, diabetes, obesity, T cell mediated autoimmune diseases, ischemia and other complications associated with these diseases and disorders The use according to claim 227, comprising a therapy for treatment in a patient.   Human treatment of cancer, systemic or chronic inflammation, rheumatoid arthritis, diabetes, obesity, T cell mediated autoimmune diseases, ischemia and other complications associated with these diseases and disorders The use according to claim 227, comprising a therapy for delaying the occurrence in the patient or for reducing the symptoms thereof.   200. A composition comprising a compound according to any one of claims 1 to 200 for use as a medicament.   Used in treating cancer, systemic or chronic inflammation, rheumatoid arthritis, diabetes, obesity, T cell mediated autoimmune diseases, ischemia, and other complications associated with these diseases and disorders 200. A composition comprising a compound according to any one of claims 1 to 200 for.   The composition of claim 231, for use in treating cancer.   200. A method of inhibiting the activity of Nampt in a human cell comprising the step of contacting said cell with a compound according to any one of claims 1 to 200.   234. The method of claim 233, wherein the cell is in a human patient. 200. A method of identifying a cancer that is likely to be treated with a compound according to any one of claims 1 to 200, comprising:
Obtaining a biopsy sample of the cancer;
Including the step of determining the expression level of an enzyme in the NAD biosynthetic pathway for a non-cancerous control tissue,
If the expression level of the enzyme in the pathway is reduced relative to non-cancerous control tissue, the cancer is likely to be treatable with the compound of any one of claims 1-200. A method identified as A method of making a compound comprising:

Reaction under appropriate conditions to produce an intermediate

Obtaining
The intermediate as a second intermediate

Converting to:
Reacting the second intermediate with Y- (CH ₂ ) _q -NH ₂

Including the steps of:
Wherein Y, Y ₁ , o, p, and q are as defined in claim 29; and
R ₁ and R ₂ are as defined in claim 42,
Method. A method of making a compound comprising:

Reaction under appropriate conditions to produce an intermediate

Obtaining
The intermediate as a second intermediate

Converting to:
Reacting the second intermediate with Y— (CH ₂ ) _q —NH ₂ ,

Including the steps of:
Where Y, Y ₁ , o, p, and q are as defined in claim 29, and
R ₁ , R ₃ , and R ₄ are as defined in claim 39,
Method.

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